X-154380980-C-T

Position:

• chrX-154380980-C-T

Variant summary

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

The ENST00000369842.9(EMD):​c.548C>T​(p.Pro183Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P183T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EMD ENST00000369842.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U: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 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 6 pathogenic changes around while only 1 benign (86%) in ENST00000369842.9
• 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-154380980-C-T is Pathogenic according to our data. Variant chrX-154380980-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285707.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
EMD	NM_000117.3	c.548C>T	p.Pro183Leu	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>T	p.Pro183Leu	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	EMD: PM1, PM2, PM5, PP4, PS3:Supporting, PS4:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2016	- -

X-linked Emery-Dreifuss muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 10393813, 17067998, 26415001, 26675233). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 285707). This variant has not been reported in the literature in individuals affected with EMD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 183 of the EMD protein (p.Pro183Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.35
MutPred		0.49		Loss of glycosylation at P183 (P = 0.0251);.;
MVP		0.82
MPC		0.97
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.20
gMVP		0.53

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;