19-9960539-T-G

Position:

• chr19-9960539-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000264828.4(COL5A3):​c.5110A>C​(p.Lys1704Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A3 ENST00000264828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30692315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A3	NM_015719.4	c.5110A>C	p.Lys1704Gln	missense_variant	67/67	ENST00000264828.4	NP_056534.2
COL5A3	XM_011528042.3	c.5107A>C	p.Lys1703Gln	missense_variant	67/67		XP_011526344.1
COL5A3	XM_017026849.2	c.2773A>C	p.Lys925Gln	missense_variant	40/40		XP_016882338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A3	ENST00000264828.4	c.5110A>C	p.Lys1704Gln	missense_variant	67/67	1	NM_015719.4	ENSP00000264828	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.5110A>C (p.K1704Q) alteration is located in exon 67 (coding exon 67) of the COL5A3 gene. This alteration results from a A to C substitution at nucleotide position 5110, causing the lysine (K) at amino acid position 1704 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.17
Sift	Benign	0.041	D
Sift4G	Benign	0.088	T
Polyphen		0.011	B
Vest4		0.12
MutPred		0.73		Loss of methylation at K1704 (P = 0.0368);
MVP		0.61
MPC		0.37
ClinPred		0.20	T
GERP RS		2.9
Varity_R		0.22
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1599520528; hg19: chr19-10071215;