rs761837954

Positions:

• chr9-134822149-C-A
• chr9-134822149-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000093.5(COL5A1):​c.4607C>A​(p.Pro1536Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,255,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Scores: Splicing: ADA: 0.6200
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4607C>A	p.Pro1536Gln	missense_variant	59/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4607C>A	p.Pro1536Gln	missense_variant	59/66		NP_001265003.1
COL5A1	XM_017014266.3	c.4607C>A	p.Pro1536Gln	missense_variant	59/65		XP_016869755.1
LOC101448202	NR_103451.2	n.71-1940G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4607C>A	p.Pro1536Gln	missense_variant	59/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4607C>A	p.Pro1536Gln	missense_variant	59/66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250880 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000159 AC: 2 AN: 1255176 Hom.: 0 Cov.: 32 AF XY: 0.00000160 AC XY: 1 AN XY: 625500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000495

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000206

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.76
Sift	Benign	0.043	D;.
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;.
Vest4		0.63
MutPred		0.38		Loss of glycosylation at P1536 (P = 0.0255);Loss of glycosylation at P1536 (P = 0.0255);
MVP		0.73
MPC		0.28
ClinPred		0.88	D
GERP RS		4.7
Varity_R		0.37
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
dbscSNV1_RF	Benign	0.51
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: rs761837954; hg19: chr9-137713995;