rs886044839

Variant names:

• chrX-154380934-C-T
• rs886044839
• NM_000117.3:c.502C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000117.3(EMD):​c.502C>T​(p.Arg168Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,097,977 control chromosomes in the GnomAD database, including 1 homozygotes. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000015 (1 hom. 3 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.79
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• heart conduction disease

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000146 (16/1097977) while in subpopulation SAS AF = 0.000203 (11/54149). AF 95% confidence interval is 0.000114. There are 1 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

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.502C>T	p.Arg168Cys	missense	Exon 6 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.502C>T	p.Arg168Cys	missense	Exon 6 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.529C>T	p.Arg177Cys	missense	Exon 6 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.526C>T	p.Arg176Cys	missense	Exon 6 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 182849 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1097977 Hom.: 1 Cov.: 32 AF XY: 0.00000826 AC XY: 3 AN XY: 363373

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.000203 AC: 11 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40261

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842140

Other (OTH) AF: 0.0000217 AC: 1 AN: 46092

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.41		Loss of MoRF binding (P = 0.0562)
MVP		0.98
MPC		1.1
ClinPred		0.70	D
GERP RS		5.2
Varity_R		0.17
gMVP		0.57
Mutation Taster		=85/15	polymorphism

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: rs886044839; hg19: chrX-153609294;