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 ENST00000369842.9(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 ENST00000369842.9 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 32 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 ENST00000369842.9 (EMD) was described as [Pathogenic] in ClinVar
• 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 VariationId is 281087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000369842.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	NM_000117.3	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 6	NP_000108.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	ENST00000369842.9	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 6	ENSP00000358857.4
	EMD	ENST00000683627.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 7	ENSP00000507533.1
	EMD	ENST00000369835.3	TSL:3	c.3G>A	p.Met1?	start_lost	Exon 1 of 5	ENSP00000358850.3

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	X-linked Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.61	D
PhyloP100		0.71
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.048	D
Polyphen		0.92	P
Vest4		0.72
MutPred		0.62		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;