rs267606782

Variant names:

• chrX-154379485-A-G
• rs267606782
• NM_000117.3:c.1A>G
• EMD p.Met1?

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1 PS1_Moderate PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000321602: protein studies have shown that c.2T>C and c.2T>G result in a lack of emerin protein expression (Yates et al., 1999" and additional evidence is available in ClinVar.

• 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:4
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• heart conduction disease

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

ACMG classification

Our verdict: Pathogenic. The variant received 24 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 33 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
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321602: 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).
• 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 VariationId is 11172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000117.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	NM_000117.3	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_000108.1	P50402

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	ENST00000369842.9	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000603592.1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	X-linked Emery-Dreifuss muscular dystrophy (2)
1	-	-	CARDIOMYOPATHY, DILATED, 3C (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.55	D
PhyloP100		0.58
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs267606782;

hg19: chrX-153607845;