rs104894806

Positions:

• chrX-154380979-C-A
• chrX-154380979-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000117.3(EMD):​c.547C>A​(p.Pro183Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P183L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.15

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Interaction with CTNNB1 (size 18) in uniprot entity EMD_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000117.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP5: Variant X-154380979-C-A is Pathogenic according to our data. Variant chrX-154380979-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154380979-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.547C>A	p.Pro183Thr	missense_variant	6/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.547C>A	p.Pro183Thr	missense_variant	6/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;T
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.0000017	A;A
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.53
Sift	Benign	0.32	T;T
Sift4G	Uncertain	0.035	D;D
Polyphen		0.99	D;.
Vest4		0.33
MutPred		0.52		Loss of glycosylation at P183 (P = 0.0662);.;
MVP		0.98
MPC		1.0
ClinPred		0.73	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.51

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: rs104894806; hg19: chrX-153609339;