rs869320625

chr1-19243991-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2 O:1
• Conservation: PhyloP100: 4.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-19243991-G-A is Pathogenic according to our data. Variant chr1-19243991-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219100.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3, not_provided=1, Pathogenic=2}. Variant chr1-19243991-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMC1	NM_015047.3	c.245C>T	p.Thr82Met	missense_variant	3/23	ENST00000477853.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMC1	ENST00000477853.6	c.245C>T	p.Thr82Met	missense_variant	3/23	1	NM_015047.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251362 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135868

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000530 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cerebellar atrophy, visual impairment, and psychomotor retardation; Pathogenic:3 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 29, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 06, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2023	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 (Marquez et al., 2020); 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, Peer-Zada2021[casereport], 32092440, 30826214, 37098815, 33236988, 30577886, 31904590) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	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. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2016

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

research

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

-

- -

EMC1-Related Disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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 v4.3

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;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.15
Sift	Benign	0.034	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.99	D;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

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

Publications

LitVar

Other links and lift over

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