Genetic Variant EMD:p.Ser8Leu (chrX-154379507-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS2

The NM_000117.3(EMD):c.23C>T(p.Ser8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,055,755 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. S8W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000019 ( 0 hom. 2 hem. )

Consequence

EMD
NM_000117.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.913

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity EMD_HUMAN

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.23C>T	p.Ser8Leu	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.23C>T	p.Ser8Leu	missense_variant	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4		P50402

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000189

AC:

AN:

1055755

Hom.:

Cov.:

AF XY:

0.00000579

AC XY:

AN XY:

345175

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24959

American (AMR)

AF:

0.00

AC:

AN:

28665

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18649

East Asian (EAS)

AF:

0.00

AC:

AN:

27277

South Asian (SAS)

AF:

0.00

AC:

AN:

50139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36931

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4063

European-Non Finnish (NFE)

AF:

0.00000244

AC:

AN:

820652

Other (OTH)

AF:

0.00

AC:

AN:

44420

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy

Uncertain:1

Nov 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with EMD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 8 of the EMD protein (p.Ser8Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Benign

0.84

DEOGEN2

Uncertain

0.65

D;T

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.86

D;T

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

0.91

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.41

MutPred

0.68

Loss of disorder (P = 0.0227);Loss of disorder (P = 0.0227);

MVP

0.90

MPC

0.90

ClinPred

0.98

GERP RS

4.0

PromoterAI

-0.070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.85

Mutation Taster

=77/23

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-154379507-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