rs886044771

Variant names:

• chrX-154379487-G-A
• rs886044771
• NM_000117.3:c.3G>A

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.3G>A​(p.Met1?) variant causes a start lost 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: 26)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: EMD NM_000117.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.711
• Publications: 1 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 11172
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154379487-G-A is Pathogenic according to our data. Variant chrX-154379487-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 281087.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.3G>A	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.3G>A	p.Met1?	start_lost	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1053028 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 344304

African (AFR) AF: 0.00 AC: 0 AN: 24747

American (AMR) AF: 0.00 AC: 0 AN: 28215

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18616

East Asian (EAS) AF: 0.00 AC: 0 AN: 27061

South Asian (SAS) AF: 0.00 AC: 0 AN: 49927

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819301

Other (OTH) AF: 0.00 AC: 0 AN: 44295

GnomAD4 genome Cov.: 26

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jun 26, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2014

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 281087). Disruption of the initiator codon has been observed in individuals with X-linked Emery-Dreifuss muscular dystrophy (PMID: 7894480, 8595406, 10399752, 19997654, 21697856). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the EMD mRNA. The next in-frame methionine is located at codon 73. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Uncertain	0.63	D;T
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.61	D
PhyloP100		0.71
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.92	P;.
Vest4		0.72
MutPred		0.62		Gain of catalytic residue at M1 (P = 0.0413);Gain of catalytic residue at M1 (P = 0.0413);
MVP		1.0
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.90
gMVP		0.72
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886044771; hg19: chrX-153607847;