chr17-50199458-G-T

Variant names:

• chr17-50199458-G-T
• rs115997082
• NM_000088.4:c.334-5C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000088.4(COL1A1):​c.334-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: COL1A1 NM_000088.4 splice_region, intron
• Scores: Splicing: ADA: 0.002057
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -0.0750
• Publications: 3 publications found

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A1 Gene-Disease associations (from GenCC):

• Caffey disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-50199458-G-T is Benign according to our data. Variant chr17-50199458-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 324119.
• BS2: High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.334-5C>A		splice_region_variant, intron_variant	Intron 3 of 50	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.334-5C>A		splice_region_variant, intron_variant	Intron 3 of 47		XP_011522643.1
COL1A1	XM_005257058.5	c.334-5C>A		splice_region_variant, intron_variant	Intron 3 of 48		XP_005257115.2
COL1A1	XM_005257059.5	c.334-5C>A		splice_region_variant, intron_variant	Intron 3 of 37		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.334-5C>A		splice_region_variant, intron_variant	Intron 3 of 50	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000474644.1	n.550C>A		non_coding_transcript_exon_variant	Exon 3 of 4	3
COL1A1	ENST00000507689.1	c.388-5C>A		splice_region_variant, intron_variant	Intron 2 of 3	2		ENSP00000460459.1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251058 AF XY: 0.000118

Gnomad AFR exome AF: 0.00223

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.0000564 AC XY: 41 AN XY: 727224

African (AFR) AF: 0.00200 AC: 67 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111982

Other (OTH) AF: 0.000199 AC: 12 AN: 60386

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74492

African (AFR) AF: 0.00183 AC: 76 AN: 41586

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000714

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 15, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the COL1A1 gene. The c.334-5 C>A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 0.2-0.3% alleles from individuals of African ancestry in large population cohorts, indicating it may be a rare benign variant in this population (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.334-5 C>A variant occurs at a nucleotide position that is not conserved across species. Additionally, in silico splice prediction algorithms are inconclusive as to whether or not this variant damages the splice acceptor site in intron 3. While other splice site variants in the COL1A1 gene have been reported in HGMD in association with COL1A1-related disorders (Stenson et al., 2014), in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL1A1: BP4, BS1, BS2

Infantile cortical hyperostosis Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Osteogenesis imperfecta Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

COL1A1-related disorder Benign:1

Mar 19, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

See cases Benign:1

Jun 10, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: BS1, BP4

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Cardiovascular phenotype Benign:1

Jan 25, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Osteogenesis imperfecta type I Benign:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.53
PhyloP100		-0.075
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115997082; hg19: chr17-48276819;