rs142890619

Variant names:

• chr9-134701277-G-A
• rs142890619
• NM_000093.5:c.598G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000093.5(COL5A1):​c.598G>A​(p.Asp200Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 9.82

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 -9 ACMG points.

• BP6: Variant 9-134701277-G-A is Benign according to our data. Variant chr9-134701277-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213015.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152276) while in subpopulation NFE AF= 0.000647 (44/68034). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.598G>A	p.Asp200Asn	missense_variant	Exon 4 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.598G>A	p.Asp200Asn	missense_variant	Exon 4 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.598G>A	p.Asp200Asn	missense_variant	Exon 4 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.598G>A	p.Asp200Asn	missense_variant	Exon 4 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.598G>A	p.Asp200Asn	missense_variant	Exon 4 of 66	2		ENSP00000360885.4
COL5A1	ENST00000464187.1	n.1020G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000368 AC: 92 AN: 250270 Hom.: 0 AF XY: 0.000369 AC XY: 50 AN XY: 135644

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000600 AC: 877 AN: 1461662 Hom.: 0 Cov.: 33 AF XY: 0.000567 AC XY: 412 AN XY: 727108

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000735

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74462

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Dec 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28074886, 29924831) -

May 23, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL5A1 c.598G>A (p.Asp200Asn) results in a conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 250270 control chromosomes (gnomAD). The observed variant frequency is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05), strongly suggesting that the variant is benign. c.598G>A has been reported in the literature in a sudden infant death syndrome cohort (e.g., Neubauer_2017), however without strong evidence for causality (e.g., lack of co-segregation data). These report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29924831, 28074886). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (likely benign, n = 4; VUS, n = 1). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jan 14, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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 Benign:1

Mar 03, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.41
Sift	Benign	0.045	D;.
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;.
Vest4		0.91
MVP		0.78
MPC		0.63
ClinPred		0.21	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.60

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: rs142890619; hg19: chr9-137593123; COSMIC: COSV65668021;