rs149561221

Positions:

• chr17-50192799-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000088.4(COL1A1):​c.1873G>A​(p.Ala625Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,614,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: COL1A1 NM_000088.4 missense, splice_region
• Scores: Splicing: ADA: 0.002451
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.58

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019023716).
• BP6: Variant 17-50192799-C-T is Benign according to our data. Variant chr17-50192799-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 196007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0013 (198/152262) while in subpopulation AFR AF= 0.00409 (170/41554). AF 95% confidence interval is 0.00359. There are 0 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1873G>A	p.Ala625Thr	missense_variant, splice_region_variant	27/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1675G>A	p.Ala559Thr	missense_variant, splice_region_variant	24/48		XP_011522643.1
COL1A1	XM_005257058.5	c.1873G>A	p.Ala625Thr	missense_variant, splice_region_variant	27/49		XP_005257115.2
COL1A1	XM_005257059.5	c.958-106G>A		intron_variant			XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1873G>A	p.Ala625Thr	missense_variant, splice_region_variant	27/51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000476387.1	n.222G>A		splice_region_variant, non_coding_transcript_exon_variant	3/9	2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000537 AC: 135 AN: 251208 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135838

Gnomad AFR exome AF: 0.00532

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000241 AC: 352 AN: 1461846 Hom.: 2 Cov.: 35 AF XY: 0.000228 AC XY: 166 AN XY: 727224

Gnomad4 AFR exome AF: 0.00439

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74452

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.000681 Hom.: 0

Bravo AF: 0.00141

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	- -

Osteogenesis imperfecta Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	May 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2023	Variant summary: COL1A1 c.1873G>A (p.Ala625Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 282576 control chromosomes (gnomAD), predominantly at a frequency of 0.0047 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 167 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1873G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters have assessed the variant since 2014: four classified the variant as likely benign and four as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2015	- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

COL1A1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

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). -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Infantile cortical hyperostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.35	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.31
Sift	Benign	0.19	T
Sift4G	Benign	0.37	T
Vest4		0.36
MVP		0.76
MPC		0.54
ClinPred		0.022	T
GERP RS		3.9
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.050
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

Publications

LitVar

Other links and lift over

dbSNP: rs149561221; hg19: chr17-48270160;