chrX-154379485-A-G

Variant names:

• chrX-154379485-A-G
• rs267606782
• NM_000117.3:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 2 publications found

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]

EMD Gene-Disease associations (from GenCC):

• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• heart conduction disease

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 31 pathogenic variants. Next in-frame start position is after 73 codons. Genomic position: 154379971. Lost 0.284 part of the original CDS.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4

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

African (AFR) AF: 0.00 AC: 0 AN: 24701

American (AMR) AF: 0.00 AC: 0 AN: 28169

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18602

East Asian (EAS) AF: 0.00 AC: 0 AN: 27041

South Asian (SAS) AF: 0.00 AC: 0 AN: 49908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4049

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 819098

Other (OTH) AF: 0.00 AC: 0 AN: 44274

GnomAD4 genome Cov.: 26

Alfa AF: 0.0000432 Hom.: 0

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

Dec 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 19, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the EMD mRNA. The next in-frame methionine is located at codon 73. This variant is not present in population databases (ExAC no frequency). 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). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Apr 22, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.58
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
PromoterAI		-0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.72
Mutation Taster		=6/194	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: rs267606782; hg19: chrX-153607845;