rs1553252938

Positions:

• chr1-19232655-G-C
• chr1-19232655-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_015047.3(EMC1):​c.1751C>G​(p.Pro584Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EMC1 NM_015047.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.33

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• PP5: Variant 1-19232655-G-C is Pathogenic according to our data. Variant chr1-19232655-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 801455.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC1	NM_015047.3	c.1751C>G	p.Pro584Arg	missense_variant	15/23	ENST00000477853.6	NP_055862.1
EMC1-AS1	NR_135114.1	n.175-7602G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC1	ENST00000477853.6	c.1751C>G	p.Pro584Arg	missense_variant	15/23	1	NM_015047.3	ENSP00000420608	P4
EMC1-AS1	ENST00000437898.3	n.213-7602G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 11, 2023	The c.1751C>G variant in EMC1 has not previously been reported in the literature and it has been deposited in ClinVar [ClinVar ID: 801455] as a Likely Pathogenic with cerebellar atrophy, visual impairment, and psychomotor retardation phenotype. The c.1751C>G variant is absent from population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1751C>G variant is located in exon 15 of this 23-exon gene and is predicted to replace an evolutionary conserved proline amino acid with arginine at position 584 (p.(Pro584Arg)) in the beta-propeller domain of the protein [PMID: 35234901]. In silico predictions for p.(Pro584Arg) are inconclusive of the variant's effect [(CADD v1.6 = 28.4, REVEL = 0.438)]; however, there are no functional studies to support or refute these predictions. A different missense variant p.(Pro584His) affecting the same amino acid has been reported in the literature segregating as de novo heterozygous variant in a 5 years old boy with global developmental delay, no speech, seizure, truncal hypotonia, cortical visualimpairment, roving eye movement, cerebellar atrophy, and hip dysplasia [PMID:35234901] and in ClinVar [ClinVar ID: 521479] as a Likely Pathogenic in a male individual with severe global developmental delay, cortical visual impairment, and generalized hypotonia phenotypes. Based on available evidence this de novo c.1751C>G p.(Pro584Arg) variant identified in EMC1 is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;P;P
Vest4		0.89
MutPred		0.51		Gain of solvent accessibility (P = 0.0584);.;.;
MVP		0.68
MPC		1.0
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.63
gMVP		0.64

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: rs1553252938; hg19: chr1-19559149;