rs2228559

Positions:

• chr9-134822102-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000093.5(COL5A1):​c.4560C>T​(p.Ile1520=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,196 control chromosomes in the GnomAD database, including 793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (118 hom., cov: 33)
  • Exomes 𝑓: 0.028 (675 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.368

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-134822102-C-T is Benign according to our data. Variant chr9-134822102-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134822102-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.368 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.4560C>T	p.Ile1520=	synonymous_variant	59/66	ENST00000371817.8
LOC101448202	NR_103451.2	n.71-1893G>A		intron_variant, non_coding_transcript_variant
COL5A1	NM_001278074.1	c.4560C>T	p.Ile1520=	synonymous_variant	59/66
COL5A1	XM_017014266.3	c.4560C>T	p.Ile1520=	synonymous_variant	59/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.4560C>T	p.Ile1520=	synonymous_variant	59/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.4560C>T	p.Ile1520=	synonymous_variant	59/66	2		A2

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5305 AN: 152166 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0364

GnomAD3 exomes AF: 0.0256 AC: 6429 AN: 251446 Hom.: 139 AF XY: 0.0250 AC XY: 3396 AN XY: 135896

Gnomad AFR exome AF: 0.0654

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0503

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.0175

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0278 AC: 40627 AN: 1460912 Hom.: 675 Cov.: 32 AF XY: 0.0275 AC XY: 19976 AN XY: 726792

Gnomad4 AFR exome AF: 0.0665

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0513

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.0216

Gnomad4 NFE exome AF: 0.0286

Gnomad4 OTH exome AF: 0.0301

GnomAD4 genome AF: 0.0349 AC: 5311 AN: 152284 Hom.: 118 Cov.: 33 AF XY: 0.0327 AC XY: 2436 AN XY: 74464

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0531

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.0205

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0320 Hom.: 47

Bravo AF: 0.0354

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0248

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2012	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. -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 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

Jan 30, 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 type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 07, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 15, 2017

Variant summary: The c.4560C>T (p.Ile1520=) in COL5A1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect the normal splicing pattern, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.02718 (3299 /121364 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.000031). The variant of interest has been cited as Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.73

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: rs2228559; hg19: chr9-137713948;