rs2228559

Positions:

chr9-134822102-C-T

Variant summary

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

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.368

Variant links:

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]

COL5A1 links:

LOC101448202 (HGNC:):

LOC101448202 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=-0.33).

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	Protein
COL5A1	NM_000093.5 linkuse as main transcript	c.4560C>T	p.Ile1520=	synonymous_variant	59/66	ENST00000371817.8	NP_000084.3
LOC101448202	NR_103451.2 linkuse as main transcript	n.71-1893G>A		intron_variant, non_coding_transcript_variant
COL5A1	NM_001278074.1 linkuse as main transcript	c.4560C>T	p.Ile1520=	synonymous_variant	59/66		NP_001265003.1
COL5A1	XM_017014266.3 linkuse as main transcript	c.4560C>T	p.Ile1520=	synonymous_variant	59/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.4560C>T	p.Ile1520=	synonymous_variant	59/66	1	NM_000093.5	ENSP00000360882	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.4560C>T	p.Ile1520=	synonymous_variant	59/66	2		ENSP00000360885	A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.0349

AC:

5305

AN:

152166

Hom.:

116

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0275

AC XY:

19976

AN XY:

726792

show subpopulations

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.:

AF XY:

0.0327

AC XY:

2436

AN XY:

74464

show subpopulations

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.:

Bravo

AF:

0.0354

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0218

EpiControl

AF:

0.0248

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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, 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. -

not provided

Benign:2

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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 07, 2022

- -

Ehlers-Danlos syndrome type 7A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

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

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