rs369396868

Variant names:

• chr9-134701205-A-C
• rs369396868
• NM_000093.5:c.526A>C

Variant summary

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

The NM_000093.5(COL5A1):​c.526A>C​(p.Asn176His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,908 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 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 9.16

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 9-134701205-A-C is Benign according to our data. Variant chr9-134701205-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451730.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000591 (9/152224) while in subpopulation SAS AF= 0.00125 (6/4812). AF 95% confidence interval is 0.000543. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.526A>C	p.Asn176His	missense_variant	Exon 4 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.526A>C	p.Asn176His	missense_variant	Exon 4 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.526A>C	p.Asn176His	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.526A>C	p.Asn176His	missense_variant	Exon 4 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.526A>C	p.Asn176His	missense_variant	Exon 4 of 66	2		ENSP00000360885.4
COL5A1	ENST00000464187.1	n.948A>C		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250564 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74426

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Apr 03, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N176H variant (also known as c.526A>C), located in coding exon 4 of the COL5A1 gene, results from an A to C substitution at nucleotide position 526. The asparagine at codon 176 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Sep 01, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the COL5A1 gene. The N176H variant has not been published as pathogenic or been reported as benign to our knowledge. N176H has been observed in 5/8,606 (0.06%) alleles form individuals of East Asian ancestry in the Exome Aggregation Consortium (Lek et al., 2016). The N176H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the N176H variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). -

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

Jan 09, 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.028	D;.
Sift4G	Uncertain	0.014	D;D
Polyphen		0.99	D;.
Vest4		0.58
MutPred		0.68		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.84
MPC		0.65
ClinPred		0.22	T
GERP RS		5.2
Varity_R		0.16
gMVP		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: rs369396868; hg19: chr9-137593051;