rs267606782

chrX-154379485-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000117.3(EMD):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000095 in 1,052,630 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: EMD NM_000117.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.580

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000117.3 (EMD) was described as [Pathogenic] in ClinVar as 281087
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154379485-A-G is Pathogenic according to our data. Variant chrX-154379485-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154379485-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.1A>G	p.Met1?	start_lost	1/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.1A>G	p.Met1?	start_lost	1/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 9.50e-7 AC: 1 AN: 1052630 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 344126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000122

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 19, 2019	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in a several individuals affected with Emery-Dreifuss muscular dystrophy (PMID: 7894480, 19997654, 21697856). ClinVar contains an entry for this variant (Variation ID: 11172). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the EMD mRNA. The next in-frame methionine is located at codon 73. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2016

The c.1 A>G variant in the EMD gene has been reported in association with X-linked Emery-Dreifuss muscular dystrophy (EDMD) (Bione et al., 1994; Brown et al., 2011). This variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. Other variants altering the initiator Methionine codon (c.2T>C, c.2T>G, c.3G>A) have been reported in HGMD in association with EDMD (Stenson P et al., 2014) and protein studies have shown that c.2T>C and c.2T>G result in a lack of emerin protein expression (Yates et al., 1999; Manilal et al. 1998). Furthermore, the c.1 A>G variant was not observed in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, we interpret c.1 A>G in the EMD gene as pathogenic." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Benign	19
Dann	Benign	0.66
DEOGEN2	Uncertain	0.65	D;T
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.92	P;.
Vest4		0.79
MutPred		0.62		Loss of stability (P = 0.1127);Loss of stability (P = 0.1127);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.72

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: rs267606782; hg19: chrX-153607845;