rs77176843

chr9-134817837-G-Achr9-134817837-G-Cchr9-134817837-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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:11
• Conservation: PhyloP100: -0.132

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 3945 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.4230+6G>A		splice_donor_region_variant, intron_variant		ENST00000371817.8
COL5A1	NM_001278074.1	c.4230+6G>A		splice_donor_region_variant, intron_variant
COL5A1	XM_017014266.3	c.4230+6G>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.4230+6G>A		splice_donor_region_variant, intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.4230+6G>A		splice_donor_region_variant, intron_variant		2		A2

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3945 AN: 152232 Hom.: 91 Cov.: 33

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

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.: 33 AF XY: 0.0346 AC XY: 24871 AN XY: 719678

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.: 91 Cov.: 33 AF XY: 0.0251 AC XY: 1867 AN XY: 74502

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.: 52

Bravo AF: 0.0220

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
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	-	- -

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	Invitae	Feb 01, 2024	- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 20, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

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

Other links and lift over

dbSNP: rs77176843; hg19: chr9-137709683; COSMIC: COSV65674178;