rs2229817

Positions:

• chr9-134835104-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.5270C>T​(p.Thr1757Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,613,724 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1757T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (185 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.33

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

LOC101448202 (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), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027009249).
• BP6: Variant 9-134835104-C-T is Benign according to our data. Variant chr9-134835104-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134835104-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.5270C>T	p.Thr1757Met	missense_variant	65/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.5270C>T	p.Thr1757Met	missense_variant	65/66		NP_001265003.1
LOC101448202	NR_103451.2	n.71-14895G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.5270C>T	p.Thr1757Met	missense_variant	65/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.5270C>T	p.Thr1757Met	missense_variant	65/66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 768 AN: 152212 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.0913

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0120 AC: 3016 AN: 250710 Hom.: 71 AF XY: 0.0117 AC XY: 1588 AN XY: 135740

Gnomad AFR exome AF: 0.000803

Gnomad AMR exome AF: 0.00958

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.0878

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000812

Gnomad OTH exome AF: 0.00916

GnomAD4 exome AF: 0.00486 AC: 7105 AN: 1461394 Hom.: 185 Cov.: 33 AF XY: 0.00529 AC XY: 3849 AN XY: 727046

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00863

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.0795

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.000321

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.00969

GnomAD4 genome AF: 0.00504 AC: 768 AN: 152330 Hom.: 26 Cov.: 33 AF XY: 0.00569 AC XY: 424 AN XY: 74478

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.0917

Gnomad4 SAS AF: 0.0211

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00434 Hom.: 22

Bravo AF: 0.00530

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.0119 AC: 1448

Asia WGS AF: 0.0750 AC: 264 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2013	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2017	Variant summary: The COL5A1 c.5270C>T (p.Thr1757Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1444/119592 control chromosomes (24 homozygotes) at a frequency of 0.0120744, which is approximately 9660 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, based on the prevalence in general population this variant is classified as benign. -

Ehlers-Danlos syndrome, classic type, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2015

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. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

Ehlers-Danlos syndrome type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome, classic 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.044	D;D
Polyphen		0.99	D;.
Vest4		0.18
MPC		0.31
ClinPred		0.013	T
GERP RS		5.0
Varity_R		0.32
gMVP		0.49

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

Other links and lift over

dbSNP: rs2229817; hg19: chr9-137726950; COSMIC: COSV65669124; COSMIC: COSV65669124;