rs45556931

Variant names:

• chr9-134812587-G-A
• rs45556931
• NM_000093.5:c.3745-18G>A

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.3745-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,609,704 control chromosomes in the GnomAD database, including 7,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1004 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6203 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.381

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=-0.84).
• BP6: Variant 9-134812587-G-A is Benign according to our data. Variant chr9-134812587-G-A is described in ClinVar as [Benign]. Clinvar id is 136881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134812587-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.3745-18G>A		intron_variant	Intron 47 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.3745-18G>A		intron_variant	Intron 47 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.3745-18G>A		intron_variant	Intron 47 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.3745-18G>A		intron_variant	Intron 47 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.3745-18G>A		intron_variant	Intron 47 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16048 AN: 152084 Hom.: 1000 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0869

Gnomad OTH AF: 0.0985

GnomAD3 exomes AF: 0.0865 AC: 21057 AN: 243376 Hom.: 1027 AF XY: 0.0877 AC XY: 11575 AN XY: 132016

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.0433

Gnomad ASJ exome AF: 0.0998

Gnomad EAS exome AF: 0.0362

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.0909

Gnomad NFE exome AF: 0.0899

Gnomad OTH exome AF: 0.0886

GnomAD4 exome AF: 0.0897 AC: 130739 AN: 1457502 Hom.: 6203 Cov.: 32 AF XY: 0.0898 AC XY: 65091 AN XY: 724964

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.0460

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0527

Gnomad4 SAS exome AF: 0.0975

Gnomad4 FIN exome AF: 0.0891

Gnomad4 NFE exome AF: 0.0891

Gnomad4 OTH exome AF: 0.0921

GnomAD4 genome AF: 0.106 AC: 16068 AN: 152202 Hom.: 1004 Cov.: 33 AF XY: 0.103 AC XY: 7687 AN XY: 74426

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0378

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.0851

Gnomad4 NFE AF: 0.0869

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0936 Hom.: 133

Bravo AF: 0.104

Asia WGS AF: 0.0950 AC: 329 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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.3745-18G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 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 10405/96166 control chromosomes (521 homozygotes) at a frequency of 0.1081983, which is approximately 86559 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. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromuscular dysplasia, multifocal Benign:1

Mar 15, 2022

Genome-Nilou Lab

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	-0.84
CADD	Benign	5.6
DANN	Benign	0.50

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: rs45556931; hg19: chr9-137704433;