rs104894805

Positions:

• chrX-154380980-C-A
• chrX-154380980-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000117.3(EMD):​c.548C>A​(p.Pro183His) variant causes a missense change involving the alteration of a non-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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.48

Genes affected

EMD (HGNC:3331): (emerin) Emerin is a serine-rich nuclear membrane protein and a member of the nuclear lamina-associated protein family. It mediates membrane anchorage to the cytoskeleton. Dreifuss-Emery muscular dystrophy is an X-linked inherited degenerative myopathy resulting from mutation in the emerin gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant X-154380980-C-A is Pathogenic according to our data. Variant chrX-154380980-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154380980-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMD	NM_000117.3	c.548C>A	p.Pro183His	missense_variant	6/6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.548C>A	p.Pro183His	missense_variant	6/6	1	NM_000117.3	ENSP00000358857	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 28, 2019	This variant has been reported to affect EMD protein function (PMID: 10393813, 17067998, 26415001, 26675233). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro183 amino acid residue in EMD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10382909, 10393813, 26415001, 26675233). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been observed in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 10323252). ClinVar contains an entry for this variant (Variation ID: 11178). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with histidine at codon 183 of the EMD protein (p.Pro183His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.64	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	2.5e-7	A;A
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.45
MutPred		0.55		Loss of glycosylation at P183 (P = 0.0251);.;
MVP		0.95
MPC		1.0
ClinPred		0.94	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.52

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: rs104894805; hg19: chrX-153609340;