rs1553252938

Variant names:

• chr1-19232655-G-C
• rs1553252938
• NM_015047.3:c.1751C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P584A) has been classified as Uncertain significance.

• 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:2
• Conservation: PhyloP100: 9.33
• Publications: 0 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-AS1 (HGNC:54050): (EMC1 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-19232655-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521479.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 VariationId is 801455.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC1	NM_015047.3	MANE Select	c.1751C>G	p.Pro584Arg	missense	Exon 15 of 23	NP_055862.1	Q8N766-1
	EMC1	NM_001375820.1		c.1760C>G	p.Pro587Arg	missense	Exon 16 of 24	NP_001362749.1	H7C5A2
	EMC1	NM_001375821.1		c.1757C>G	p.Pro586Arg	missense	Exon 16 of 24	NP_001362750.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC1	ENST00000477853.6	TSL:1 MANE Select	c.1751C>G	p.Pro584Arg	missense	Exon 15 of 23	ENSP00000420608.1	Q8N766-1
	EMC1	ENST00000375199.7	TSL:1	c.1748C>G	p.Pro583Arg	missense	Exon 15 of 23	ENSP00000364345.3	Q8N766-2
	EMC1	ENST00000911107.1		c.1751C>G	p.Pro584Arg	missense	Exon 15 of 24	ENSP00000581166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Cerebellar atrophy, visual impairment, and psychomotor retardation; (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
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
Mutation Taster		=40/60	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553252938; hg19: chr1-19559149;