Genetic Variant EMD:p.Leu7Phe (chrX-154379503-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_000117.3(EMD):c.19C>T(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,055,332 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. L7H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000028 ( 0 hom. 2 hem. )

Consequence

EMD
NM_000117.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00400

Publications

0 publications found

Variant links:

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

EMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3 link	c.19C>T	p.Leu7Phe	missense_variant	Exon 1 of 6	ENST00000369842.9	NP_000108.1	P50402

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9 link	c.19C>T	p.Leu7Phe	missense_variant	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4		P50402

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1055332

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

345020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24916

American (AMR)

AF:

0.0000350

AC:

AN:

28602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18641

East Asian (EAS)

AF:

0.00

AC:

AN:

27228

South Asian (SAS)

AF:

0.00

AC:

AN:

50111

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4067

European-Non Finnish (NFE)

AF:

0.00000244

AC:

AN:

820455

Other (OTH)

AF:

0.00

AC:

AN:

44388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4_mod, PM2, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Uncertain

0.64

D;T

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

0.0040

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.0

D;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.21

T;D

Polyphen

1.0

D;.

Vest4

0.35

MutPred

0.78

Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);

MVP

0.55

MPC

1.0

ClinPred

0.49

GERP RS

3.1

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.49

gMVP

0.81

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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X-154379503-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over