rs869320625

Variant names:

• chr1-19243991-G-A
• rs869320625
• NM_015047.3:c.245C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-19243991-G-A
• chr1-19243991-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_015047.3(EMC1):​c.245C>T​(p.Thr82Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T82T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: EMC1 NM_015047.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 4.93
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• cerebellar atrophy, visual impairment, and psychomotor retardation;

  Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• complex neurodevelopmental disorder with motor features

  Inheritance: AD, AR Classification: MODERATE Submitted by: ClinGen
• global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 1-19243991-G-A is Pathogenic according to our data. Variant chr1-19243991-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015047.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC1	NM_015047.3	MANE Select	c.245C>T	p.Thr82Met	missense	Exon 3 of 23	NP_055862.1
	EMC1	NM_001375820.1		c.245C>T	p.Thr82Met	missense	Exon 3 of 24	NP_001362749.1
	EMC1	NM_001375821.1		c.245C>T	p.Thr82Met	missense	Exon 3 of 24	NP_001362750.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC1	ENST00000477853.6	TSL:1 MANE Select	c.245C>T	p.Thr82Met	missense	Exon 3 of 23	ENSP00000420608.1
	EMC1	ENST00000375199.7	TSL:1	c.245C>T	p.Thr82Met	missense	Exon 3 of 23	ENSP00000364345.3
	EMC1	ENST00000486405.2	TSL:2	c.245C>T	p.Thr82Met	missense	Exon 3 of 24	ENSP00000419345.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251362 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000327 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebellar atrophy, visual impairment, and psychomotor retardation; Pathogenic:4

Lifecell International Pvt. Ltd

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Heterozygous Missense variant c.245C>T in Exon 3 of the EMC1 gene that results in the amino acid substitution p.Thr82Met was identified. The observed variant has a minor allele frequency of 0.00002% in gnomAD exomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as conflictingInterpretations of Pathogenicity(Variant ID 219100).This variant has been previously reported in Baker et al., 2019. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

Jun 09, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 29, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 06, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EMC1 (KIAA0090) c.245C>T (p.Thr82Met) results in a non-conservative amino acid change located in the Pyrrolo-quinoline quinone repeat (IPR002372) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251362 control chromosomes (gnomAD). c.245C>T has been reported in the literature in at least 4 homozygous individuals affected with Cerebellar Atrophy, Visual Impairment, And Psychomotor Retardation (Harel_2016, Baker_2019). Three of these individuals were part of the same family where the variant was found to co-segregate with disease (Harel_2016). These data indicate that the variant is likely to be associated with disease. A functional study demonstrated the variant was not able to restore sox10 expression and tadpole movement in emc1-depleted Xenopus embryos (authors assayed the expression of sox10 as a marker of effects on neural crest cells and tadpole motility as a marker of broader neurodevelopmental function) (Marquez_2020). Another study reported the variant to result in depletion of the N-cytoplasmic polytopic client (TMEM97) (Miller-Vedam_2020). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

not provided Pathogenic:2

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 82 of the EMC1 protein (p.Thr82Met). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive EMC1-related disorders (PMID: 26942288; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219100). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.

Aug 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate p.(T82M) mRNA did not significantly restore SOX10 expression, a measure of EMC1 function, and significantly reduced motility in a Xenopus model (PMID: 31904590); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29271071, 26942288, 34426522, 35234901, 32092440, Peer-Zada2021[casereport], 30826214, 37098815, 33236988, 30577886, 31904590)

Inborn genetic diseases Pathogenic:1

Mar 03, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

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

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

EMC1-related disorder Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Likely pathogenic and reported on 06/18/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.15
Sift	Benign	0.034	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.82
MVP		0.78
MPC		0.97
ClinPred		0.77	D
GERP RS		5.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.049
gMVP		0.47
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869320625; hg19: chr1-19570485; COSMIC: COSV100617458; COSMIC: COSV100617458;