rs61729495

chr9-134842193-G-Achr9-134842193-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):c.5407G>A(p.Asp1803Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000678 in 1,613,872 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.06

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]

LOC101448202 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.005375862).
• BP6: Variant 9-134842193-G-A is Benign according to our data. Variant chr9-134842193-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134842193-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00356 (541/151990) while in subpopulation AFR AF= 0.0123 (508/41422). AF 95% confidence interval is 0.0114. There are 2 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 540 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.5407G>A	p.Asp1803Asn	missense_variant	66/66	ENST00000371817.8
LOC101448202	NR_103451.2	n.71-21984C>T		intron_variant, non_coding_transcript_variant
COL5A1	NM_001278074.1	c.5407G>A	p.Asp1803Asn	missense_variant	66/66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.5407G>A	p.Asp1803Asn	missense_variant	66/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.5407G>A	p.Asp1803Asn	missense_variant	66/66	2		A2

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 540 AN: 151872 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.000899 AC: 226 AN: 251418 Hom.: 0 AF XY: 0.000721 AC XY: 98 AN XY: 135906

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000378 AC: 553 AN: 1461882 Hom.: 1 Cov.: 33 AF XY: 0.000319 AC XY: 232 AN XY: 727240

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00356 AC: 541 AN: 151990 Hom.: 2 Cov.: 32 AF XY: 0.00365 AC XY: 271 AN XY: 74314

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.00394

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00110 AC: 134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	- -

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	Jan 31, 2024	- -

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

Aug 21, 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 25, 2022

- -

Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	19
Dann	Benign	0.69
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	N;N
MutationTaster	Benign	0.59	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.4	N;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;.
Sift4G	Benign	0.93	T;T
Polyphen		0.0	B;.
Vest4		0.095
MVP		0.25
MPC		0.29
ClinPred		0.019	T
GERP RS		2.6
Varity_R		0.057
gMVP		0.26

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: rs61729495; hg19: chr9-137734039; COSMIC: COSV100879970;