Genetic Variant EMD:p.Ala5Ala (chrX-154379499-A-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_000117.3(EMD):c.15A>G(p.Ala5Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000171 in 1,168,106 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 26)

Exomes 𝑓: 9.5e-7 ( 0 hom. 0 hem. )

Consequence

EMD
NM_000117.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.17

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 -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.04).

BP6

Variant X-154379499-A-G is Benign according to our data. Variant chrX-154379499-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1543558.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.17 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3 link	c.15A>G	p.Ala5Ala	synonymous_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.15A>G	p.Ala5Ala	synonymous_variant	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4		P50402

Frequencies

GnomAD3 genomes

AF:

0.00000882

AC:

AN:

113316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000278

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000864

AC:

AN:

115723

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.48e-7

AC:

AN:

1054790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

344864

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24879

American (AMR)

AF:

0.00

AC:

AN:

28519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18628

East Asian (EAS)

AF:

0.0000368

AC:

AN:

27199

South Asian (SAS)

AF:

0.00

AC:

AN:

50078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4063

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

820146

Other (OTH)

AF:

0.00

AC:

AN:

44356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000882

AC:

AN:

113316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31292

American (AMR)

AF:

0.00

AC:

AN:

10867

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.000278

AC:

AN:

3597

South Asian (SAS)

AF:

0.00

AC:

AN:

2866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53267

Other (OTH)

AF:

0.00

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy

Benign:1

Apr 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

9.7

(source)

DANN

Benign

0.51

PhyloP100

-1.2

PromoterAI

0.0039

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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-154379499-A-G

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