1-19219329-T-TCA

Position:

• chr1-19219329-T-TCA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_015047.3(EMC1):​c.2954_2955dupTG​(p.Lys986fs) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V985V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EMC1 NM_015047.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.13

Genes affected

EMC1 (HGNC:28957): (ER membrane protein complex subunit 1) This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2012]

EMC1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00905 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-19219329-T-TCA is Pathogenic according to our data. Variant chr1-19219329-T-TCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817005.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC1	NM_015047.3	c.2954_2955dupTG	p.Lys986fs	frameshift_variant	23/23	ENST00000477853.6	NP_055862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC1	ENST00000477853.6	c.2954_2955dupTG	p.Lys986fs	frameshift_variant	23/23	1	NM_015047.3	ENSP00000420608.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

The c.2954_2955dupTG variant in the EMC1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2954_2955dupTG variant causes a frameshift , changing codon Lysine 986 to a premature Stop codon, denoted p.Lys986Ter. This variant is predicted to cause loss of normal protein function through protein truncation. The c.2954_2955dupTG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.2954_2955dupTG as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1571963780; hg19: chr1-19545823;