chr2-188985740-C-A

Position:

• chr2-188985740-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000090.4(COL3A1):​c.409C>A​(p.Pro137Thr) 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. 12/21 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: COL3A1 NM_000090.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ 4.0879 (greater than the threshold 3.09). Trascript score misZ 4.5995 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13706246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.409C>A	p.Pro137Thr	missense_variant	4/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.409C>A	p.Pro137Thr	missense_variant	4/51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.409C>A	p.Pro137Thr	missense_variant	4/50	1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 14, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with COL3A1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 137 of the COL3A1 protein (p.Pro137Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.49	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.23
Sift	Benign	0.20	T;T
Sift4G	Benign	0.064	T;T
Polyphen		0.34	B;.
Vest4		0.27
MutPred		0.34		Gain of phosphorylation at P137 (P = 0.0093);Gain of phosphorylation at P137 (P = 0.0093);
MVP		0.74
MPC		0.70
ClinPred		0.48	T
GERP RS		-1.8
Varity_R		0.12
gMVP		0.13

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: rs1553506950; hg19: chr2-189850466;