rs869320624

chr1-19220813-TAGGA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015047.3(EMC1):c.2619_2622del(p.Pro874ArgfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: EMC1 NM_015047.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.17

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-AS1 (HGNC:54050): (EMC1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-19220813-TAGGA-T is Pathogenic according to our data. Variant chr1-19220813-TAGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-19220813-TAGGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMC1	NM_015047.3	c.2619_2622del	p.Pro874ArgfsTer21	frameshift_variant	21/23	ENST00000477853.6
EMC1-AS1	NR_135114.1	n.174+10258_174+10261del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMC1	ENST00000477853.6	c.2619_2622del	p.Pro874ArgfsTer21	frameshift_variant	21/23	1	NM_015047.3	P4
EMC1-AS1	ENST00000437898.3	n.212+10258_212+10261del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151596 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151596 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74010

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, flagged submission	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2021	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 219099). This premature translational stop signal has been observed in individual(s) with EMC1-related conditions (PMID: 26942288). This sequence change creates a premature translational stop signal (p.Pro874Argfs*21) in the EMC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EMC1 are known to be pathogenic (PMID: 26572623, 26942288, 29271071). -

Cerebellar atrophy, visual impairment, and psychomotor retardation; Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 29, 2016

- -

Congenital anomaly of kidney and urinary tract Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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- -

Computational scores

Source: dbNSFP v4.3

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: rs869320624; hg19: chr1-19547307;