19-9966613-C-G

Variant names:

• chr19-9966613-C-G
• rs768803819
• NM_015719.4:c.4592G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015719.4(COL5A3):​c.4592G>C​(p.Arg1531Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,387,046 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: COL5A3 NM_015719.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.415

Genes affected

COL5A3 (HGNC:14864): (collagen type V alpha 3 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. Mutations in this gene are thought to be responsible for the symptoms of a subset of patients with Ehlers-Danlos syndrome type III. Messages of several sizes can be detected in northern blots but sequence information cannot confirm the identity of the shorter messages. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A3	NM_015719.4	c.4592G>C	p.Arg1531Pro	missense_variant	Exon 63 of 67	ENST00000264828.4	NP_056534.2
COL5A3	XM_011528042.3	c.4589G>C	p.Arg1530Pro	missense_variant	Exon 63 of 67		XP_011526344.1
COL5A3	XM_017026849.2	c.2255G>C	p.Arg752Pro	missense_variant	Exon 36 of 40		XP_016882338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A3	ENST00000264828.4	c.4592G>C	p.Arg1531Pro	missense_variant	Exon 63 of 67	1	NM_015719.4	ENSP00000264828.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1387046 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 684606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.00032	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.77	P
Vest4		0.33
MutPred		0.59		Gain of glycosylation at R1531 (P = 0.0635);
MVP		0.69
MPC		2.1
ClinPred		1.0	D
GERP RS		0.036
Varity_R		0.92
gMVP		0.81

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: rs768803819; hg19: chr19-10077289;