NM_000093.5:c.4176+9T>G

Variant names:

• chr9-134817088-T-G
• rs10858282
• NM_000093.5:c.4176+9T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.4176+9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,609,628 control chromosomes in the GnomAD database, including 111,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8236 hom., cov: 33)
  • Exomes 𝑓: 0.37 (103374 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.823

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 9-134817088-T-G is Benign according to our data. Variant chr9-134817088-T-G is described in ClinVar as [Benign]. Clinvar id is 136891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134817088-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4176+9T>G		intron_variant	Intron 53 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4176+9T>G		intron_variant	Intron 53 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.4176+9T>G		intron_variant	Intron 53 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4176+9T>G		intron_variant	Intron 53 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4176+9T>G		intron_variant	Intron 53 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48186 AN: 151964 Hom.: 8235 Cov.: 33

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.327

GnomAD3 exomes AF: 0.343 AC: 86015 AN: 251026 Hom.: 15246 AF XY: 0.345 AC XY: 46816 AN XY: 135728

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.342

Gnomad SAS exome AF: 0.305

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.373 AC: 543233 AN: 1457548 Hom.: 103374 Cov.: 33 AF XY: 0.372 AC XY: 269826 AN XY: 725302

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.305

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.392

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome AF: 0.317 AC: 48202 AN: 152080 Hom.: 8236 Cov.: 33 AF XY: 0.313 AC XY: 23259 AN XY: 74342

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.393

Gnomad4 OTH AF: 0.327

Alfa AF: 0.357 Hom.: 5620

Bravo AF: 0.311

Asia WGS AF: 0.288 AC: 1005 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 10, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The COL5A1 c.4176+9T>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 41350/120980 control chromosomes (7355 homozygotes) at a frequency of 0.341792, which is approximately 273433 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromuscular dysplasia, multifocal Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome type 7A Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.041
DANN	Benign	0.36

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: rs10858282; hg19: chr9-137708934; COSMIC: COSV65666839;