2-188974492-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000090.4(COL3A1):​c.4delA​(p.Met2fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Consequence

COL3A1
NM_000090.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.07
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 124 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-188974492-GA-G is Pathogenic according to our data. Variant chr2-188974492-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 2824645.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL3A1NM_000090.4 linkc.4delA p.Met2fs frameshift_variant Exon 1 of 51 ENST00000304636.9 NP_000081.2 P02461-1
LOC105373791XR_007087614.1 linkn.110-4014delT intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL3A1ENST00000304636.9 linkc.4delA p.Met2fs frameshift_variant Exon 1 of 51 1 NM_000090.4 ENSP00000304408.4 P02461-1
COL3A1ENST00000450867.2 linkc.4delA p.Met2fs frameshift_variant Exon 1 of 50 1 ENSP00000415346.2 H7C435
COL3A1ENST00000470167.1 linkn.100delA non_coding_transcript_exon_variant Exon 1 of 2 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:1
Jun 23, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met2*) in the COL3A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). This premature translational stop signal has been observed in individual(s) with Ehlers-Danlos syndrome (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-189839218; API