Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate

The NM_000117.3(EMD):c.548C>A(p.Pro183His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P183S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Consequence

EMD
NM_000117.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.48

Publications

18 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_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154380980-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285707.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

PP5

Variant X-154380980-C-A is Pathogenic according to our data. Variant chrX-154380980-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11178.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	NM_000117.3	MANE Select	c.548C>A	p.Pro183His	missense	Exon 6 of 6	NP_000108.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EMD	ENST00000369842.9	TSL:1 MANE Select	c.548C>A	p.Pro183His	missense	Exon 6 of 6	ENSP00000358857.4
EMD	ENST00000683627.1		c.548C>A	p.Pro183His	missense	Exon 6 of 7	ENSP00000507533.1
EMD	ENST00000369835.3	TSL:3	c.443C>A	p.Pro148His	missense	Exon 5 of 5	ENSP00000358850.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked Emery-Dreifuss muscular dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

1.6

PhyloP100

1.5

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.53

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.45

MutPred

0.55

Loss of glycosylation at P183 (P = 0.0251)

MVP

0.95

MPC

1.0

ClinPred

0.94

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.52

Mutation Taster

=23/77

disease causing (ClinVar)

(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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rs104894805

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over