rs962170388

Positions:

• chr9-134731622-G-A
• chr9-134731622-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_000093.5(COL5A1):​c.1291G>A​(p.Gly431Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000308 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G431E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 5.89

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 Likely_benign. Variant got -2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• BS2: High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.1291G>A	p.Gly431Arg	missense_variant	8/66	ENST00000371817.8
COL5A1	NM_001278074.1	c.1291G>A	p.Gly431Arg	missense_variant	8/66
COL5A1	XM_017014266.3	c.1291G>A	p.Gly431Arg	missense_variant	8/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.1291G>A	p.Gly431Arg	missense_variant	8/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.1291G>A	p.Gly431Arg	missense_variant	8/66	2		A2
COL5A1	ENST00000469093.1	n.30G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248882 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134748

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2021	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 459654; Landrum et al., 2016) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ehlers-Danlos syndrome, classic type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.11	T;.
Sift4G	Uncertain	0.039	D;D
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.25		Loss of glycosylation at S428 (P = 0.096);Loss of glycosylation at S428 (P = 0.096);
MVP		0.85
MPC		0.70
ClinPred		0.70	D
GERP RS		4.1
Varity_R		0.14
gMVP		0.73

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: rs962170388; hg19: chr9-137623468; COSMIC: COSV65672645;