rs138579182

Positions:

• chr9-134701253-G-A
• chr9-134701253-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.574G>A​(p.Asp192Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,818 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (41 hom., cov: 33)
  • Exomes 𝑓: 0.020 (378 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.18

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]

COL5A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070186555).
• BP6: Variant 9-134701253-G-A is Benign according to our data. Variant chr9-134701253-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134701253-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2362/152148) while in subpopulation NFE AF= 0.0223 (1519/68002). AF 95% confidence interval is 0.0214. There are 41 homozygotes in gnomad4. There are 1222 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.574G>A	p.Asp192Asn	missense_variant	4/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.574G>A	p.Asp192Asn	missense_variant	4/66		NP_001265003.1
COL5A1	XM_017014266.3	c.574G>A	p.Asp192Asn	missense_variant	4/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.574G>A	p.Asp192Asn	missense_variant	4/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.574G>A	p.Asp192Asn	missense_variant	4/66	2		ENSP00000360885.4
COL5A1	ENST00000464187.1	n.996G>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2361 AN: 152030 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.00307

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0167 AC: 4170 AN: 250328 Hom.: 58 AF XY: 0.0167 AC XY: 2263 AN XY: 135700

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00712

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0198 AC: 28903 AN: 1461670 Hom.: 378 Cov.: 33 AF XY: 0.0195 AC XY: 14172 AN XY: 727112

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00748

Gnomad4 FIN exome AF: 0.0470

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0155 AC: 2362 AN: 152148 Hom.: 41 Cov.: 33 AF XY: 0.0164 AC XY: 1222 AN XY: 74368

Gnomad4 AFR AF: 0.00306

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00706

Gnomad4 FIN AF: 0.0479

Gnomad4 NFE AF: 0.0223

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0189 Hom.: 43

Bravo AF: 0.0115

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0215 AC: 83

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0206 AC: 177

ExAC AF: 0.0167 AC: 2022

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.574G>A (p.Asp192Asn) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2009/119100 control chromosomes (28 homozygotes) at a frequency of 0.0168682, which is approximately 13495 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. To our knowledge, the variant of interest has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Ehlers-Danlos syndrome, classic type Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Ehlers-Danlos syndrome, classic type, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BP5 => Variant found in a case with an alternate molecular basis for disease. BA1 => Allele frequency is >1% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. Allele frequency is >4% in European (Finnish). -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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

Feb 05, 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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 10, 2022

- -

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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.58	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.70	N;.
REVEL	Benign	0.057
Sift	Benign	0.55	T;.
Sift4G	Benign	0.49	T;T
Polyphen		0.031	B;.
Vest4		0.072
MPC		0.21
ClinPred		0.0087	T
GERP RS		3.2
Varity_R		0.036
gMVP		0.22

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: rs138579182; hg19: chr9-137593099;