rs144842093

Variant names:

• chrX-154381040-G-A
• rs144842093
• NM_000117.3:c.608G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_000117.3(EMD):​c.608G>A​(p.Arg203His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,210,488 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 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. R203S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 39 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.86
• Publications: 3 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13711193).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000622 (7/112450) while in subpopulation EAS AF = 0.00139 (5/3586). AF 95% confidence interval is 0.000549. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 39 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.608G>A	p.Arg203His	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.608G>A	p.Arg203His	missense	Exon 6 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.635G>A	p.Arg212His	missense	Exon 6 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.632G>A	p.Arg211His	missense	Exon 6 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes AF: 0.0000623 AC: 7 AN: 112398 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000382 AC: 7 AN: 183153 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 129 AN: 1098038 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 39 AN XY: 363464

African (AFR) AF: 0.00 AC: 0 AN: 26403

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

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

East Asian (EAS) AF: 0.00381 AC: 115 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40326

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4137

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 842134

Other (OTH) AF: 0.0000434 AC: 2 AN: 46092

GnomAD4 genome AF: 0.0000622 AC: 7 AN: 112450 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34648

African (AFR) AF: 0.00 AC: 0 AN: 30985

American (AMR) AF: 0.00 AC: 0 AN: 10717

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00139 AC: 5 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53131

Other (OTH) AF: 0.00 AC: 0 AN: 1534

Alfa AF: 0.0000377 Hom.: 1

Bravo AF: 0.0000302

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.31
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.25
MVP		0.92
MPC		1.1
ClinPred		0.46	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.61
Mutation Taster		=92/8	polymorphism

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: rs144842093; hg19: chrX-153609400;