chr9-134815988-G-A

Variant names:

• chr9-134815988-G-A
• rs3827848
• NM_000093.5:c.4122G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.4122G>A​(p.Thr1374Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,610 control chromosomes in the GnomAD database, including 19,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1608 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17670 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9565
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.23

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 9-134815988-G-A is Benign according to our data. Variant chr9-134815988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134815988-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4122G>A	p.Thr1374Thr	splice_region_variant, synonymous_variant	Exon 52 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4122G>A	p.Thr1374Thr	splice_region_variant, synonymous_variant	Exon 52 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.4122G>A	p.Thr1374Thr	splice_region_variant, synonymous_variant	Exon 52 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4122G>A	p.Thr1374Thr	splice_region_variant, synonymous_variant	Exon 52 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4122G>A	p.Thr1374Thr	splice_region_variant, synonymous_variant	Exon 52 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21362 AN: 152044 Hom.: 1606 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.147 AC: 36952 AN: 251360 Hom.: 2888 AF XY: 0.147 AC XY: 19954 AN XY: 135876

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.153 AC: 223574 AN: 1461448 Hom.: 17670 Cov.: 34 AF XY: 0.153 AC XY: 111168 AN XY: 727038

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.141 AC: 21386 AN: 152162 Hom.: 1608 Cov.: 33 AF XY: 0.139 AC XY: 10307 AN XY: 74390

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.130

Alfa AF: 0.153 Hom.: 4447

Bravo AF: 0.132

Asia WGS AF: 0.144 AC: 503 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.150

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 10, 2017	Variant summary: The COL5A1 c.4122G>A (p.Thr1374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict weakening the canonical donor cite. However, these predictions have yet to be confirmed by functional studies. This variant was found in 17922/121286 control chromosomes (1465 homozygotes) at a frequency of 0.1477664, which is approximately 118213 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. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2024	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -
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

Feb 04, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3827848; hg19: chr9-137707834; COSMIC: COSV65666835;