chr17-50184491-A-G

Variant names:

• chr17-50184491-A-G
• rs1061970
• NM_000088.4:c.*1011T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000088.4(COL1A1):​c.*1011T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 227,668 control chromosomes in the GnomAD database, including 1,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1767 hom., cov: 31)
  • Exomes 𝑓: 0.14 (223 hom.)
• Consequence: COL1A1 NM_000088.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.534
• Publications: 17 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-50184491-A-G is Benign according to our data. Variant chr17-50184491-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 889152.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.*1011T>C		3_prime_UTR_variant	Exon 51 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.*1011T>C		3_prime_UTR_variant	Exon 48 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.*1011T>C		3_prime_UTR_variant	Exon 49 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.*1011T>C		3_prime_UTR_variant	Exon 38 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.*1011T>C		3_prime_UTR_variant	Exon 51 of 51	1	NM_000088.4	ENSP00000225964.6

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20074 AN: 151100 Hom.: 1768 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.139 AC: 10600 AN: 76466 Hom.: 223 Cov.: 0 AF XY: 0.138 AC XY: 4873 AN XY: 35260

African (AFR) AF: 0.0919 AC: 335 AN: 3644

American (AMR) AF: 0.0956 AC: 224 AN: 2342

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 530 AN: 4852

East Asian (EAS) AF: 0.331 AC: 3491 AN: 10534

South Asian (SAS) AF: 0.206 AC: 132 AN: 642

European-Finnish (FIN) AF: 0.124 AC: 37 AN: 298

Middle Eastern (MID) AF: 0.119 AC: 55 AN: 462

European-Non Finnish (NFE) AF: 0.107 AC: 5089 AN: 47340

Other (OTH) AF: 0.111 AC: 707 AN: 6352

GnomAD4 genome AF: 0.133 AC: 20076 AN: 151202 Hom.: 1767 Cov.: 31 AF XY: 0.137 AC XY: 10092 AN XY: 73794

African (AFR) AF: 0.101 AC: 4164 AN: 41260

American (AMR) AF: 0.102 AC: 1554 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3468

East Asian (EAS) AF: 0.484 AC: 2473 AN: 5110

South Asian (SAS) AF: 0.248 AC: 1186 AN: 4776

European-Finnish (FIN) AF: 0.127 AC: 1299 AN: 10268

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.127 AC: 8632 AN: 67784

Other (OTH) AF: 0.140 AC: 294 AN: 2094

Alfa AF: 0.122 Hom.: 1536

Bravo AF: 0.132

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis imperfecta 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. -

Ehlers-Danlos syndrome, arthrochalasia type 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. -

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. -

not provided Benign:1

May 10, 2021

GeneDx

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	-0.80
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1061970; hg19: chr17-48261852;