rs1057297

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000088.4(COL1A1):c.177G>T(p.Arg59=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,614,152 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 238 hom., cov: 33)

Exomes 𝑓: 0.015 ( 412 hom. )

Consequence

COL1A1
NM_000088.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.928

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 17-50199874-C-A is Benign according to our data. Variant chr17-50199874-C-A is described in ClinVar as [Benign]. Clinvar id is 254945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50199874-C-A is described in Lovd as [Benign]. Variant chr17-50199874-C-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.928 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL1A1	NM_000088.4 linkuse as main transcript	c.177G>T	p.Arg59=	synonymous_variant	2/51	ENST00000225964.10
COL1A1	XM_011524341.2 linkuse as main transcript	c.177G>T	p.Arg59=	synonymous_variant	2/48
COL1A1	XM_005257058.5 linkuse as main transcript	c.177G>T	p.Arg59=	synonymous_variant	2/49
COL1A1	XM_005257059.5 linkuse as main transcript	c.177G>T	p.Arg59=	synonymous_variant	2/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL1A1	ENST00000225964.10 linkuse as main transcript	c.177G>T	p.Arg59=	synonymous_variant	2/51	1	NM_000088.4	P1
COL1A1	ENST00000507689.1 linkuse as main transcript	c.231G>T	p.Arg77=	synonymous_variant	1/4	2
COL1A1	ENST00000474644.1 linkuse as main transcript	n.296G>T		non_coding_transcript_exon_variant	2/4	3
	ENST00000509943.2 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0383

AC:

5830

AN:

152160

Hom.:

238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0384

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0206

AC:

5168

AN:

251368

Hom.:

130

AF XY:

0.0201

AC XY:

2726

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0388

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

AF:

0.0148

AC:

21605

AN:

1461874

Hom.:

412

Cov.:

AF XY:

0.0154

AC XY:

11198

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0166

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0391

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.0196

GnomAD4 genome

AF:

0.0384

AC:

5841

AN:

152278

Hom.:

238

Cov.:

AF XY:

0.0374

AC XY:

2785

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.107

Gnomad4 AMR

AF:

0.0151

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0384

Gnomad4 FIN

AF:

0.0106

Gnomad4 NFE

AF:

0.0109

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.0172

Hom.:

Bravo

AF:

0.0405

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 16, 2022	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 07, 2022

- -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 08, 2017

- -

Infantile cortical hyperostosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2018

This alteration is classified as 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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over