chr19-9966613-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1531Q) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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]

ENSG00000295554 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015719.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A3	NM_015719.4	MANE Select	c.4592G>C	p.Arg1531Pro	missense	Exon 63 of 67	NP_056534.2	P25940

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A3	ENST00000264828.4	TSL:1 MANE Select	c.4592G>C	p.Arg1531Pro	missense	Exon 63 of 67	ENSP00000264828.3	P25940
	ENSG00000295554	ENST00000730923.1		n.74-17437C>G		intron	N/A

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

African (AFR) AF: 0.00 AC: 0 AN: 31562

American (AMR) AF: 0.00 AC: 0 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25158

East Asian (EAS) AF: 0.00 AC: 0 AN: 35774

South Asian (SAS) AF: 0.00 AC: 0 AN: 79238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4654

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078922

Other (OTH) AF: 0.0000173 AC: 1 AN: 57812

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.41
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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs768803819; hg19: chr19-10077289;