rs77176843

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):c.4230+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,601,504 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 91 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1088 hom. )

Consequence

COL5A1
NM_000093.5 splice_donor_region, intron

Scores

Splicing: ADA: 0.00002806

Clinical Significance

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

Conservation

PhyloP100: -0.132

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 9-134817837-G-A is Benign according to our data. Variant chr9-134817837-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134817837-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0259 (3947/152350) while in subpopulation NFE AF= 0.0412 (2805/68036). AF 95% confidence interval is 0.04. There are 91 homozygotes in gnomad4. There are 1867 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3947 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
COL5A1	NM_000093.5 linkuse as main transcript	c.4230+6G>A	splice_donor_region_variant, intron_variant	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 linkuse as main transcript	c.4230+6G>A	splice_donor_region_variant, intron_variant		NP_001265003.1
COL5A1	XM_017014266.3 linkuse as main transcript	c.4230+6G>A	splice_donor_region_variant, intron_variant		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.4230+6G>A		splice_donor_region_variant, intron_variant		1	NM_000093.5	ENSP00000360882	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.4230+6G>A		splice_donor_region_variant, intron_variant		2		ENSP00000360885	A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3945

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00782

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00475

Gnomad FIN

AF:

0.0441

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0412

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.0255

AC:

5684

AN:

222540

Hom.:

110

AF XY:

0.0250

AC XY:

3009

AN XY:

120224

show subpopulations

Gnomad AFR exome

AF:

0.00589

Gnomad AMR exome

AF:

0.00988

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.0000610

Gnomad SAS exome

AF:

0.00569

Gnomad FIN exome

AF:

0.0416

Gnomad NFE exome

AF:

0.0413

Gnomad OTH exome

AF:

0.0261

GnomAD4 exome

AF:

0.0353

AC:

51212

AN:

1449154

Hom.:

1088

Cov.:

AF XY:

0.0346

AC XY:

24871

AN XY:

719678

show subpopulations

Gnomad4 AFR exome

AF:

0.00502

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.0122

Gnomad4 EAS exome

AF:

0.0000512

Gnomad4 SAS exome

AF:

0.00594

Gnomad4 FIN exome

AF:

0.0419

Gnomad4 NFE exome

AF:

0.0416

Gnomad4 OTH exome

AF:

0.0268

GnomAD4 genome

AF:

0.0259

AC:

3947

AN:

152350

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

1867

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00779

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00517

Gnomad4 FIN

AF:

0.0441

Gnomad4 NFE

AF:

0.0412

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0334

Hom.:

Bravo

AF:

0.0220

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 20, 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

-0.85

CADD

Benign

6.4

DANN

Benign

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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