rs104894806

Variant names:

• chrX-154380979-C-A
• rs104894806
• NM_000117.3:c.547C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-154380979-C-A
• chrX-154380979-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_000117.3(EMD):​c.547C>A​(p.Pro183Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). 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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.15
• Publications: 8 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• heart conduction disease

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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.
• PP5: Variant X-154380979-C-A is Pathogenic according to our data. Variant chrX-154380979-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11179.Status of the report is no_assertion_criteria_provided, 0 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.547C>A	p.Pro183Thr	missense	Exon 6 of 6	NP_000108.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	ENST00000369842.9	TSL:1 MANE Select	c.547C>A	p.Pro183Thr	missense	Exon 6 of 6	ENSP00000358857.4
	EMD	ENST00000683627.1		c.547C>A	p.Pro183Thr	missense	Exon 6 of 7	ENSP00000507533.1
	EMD	ENST00000369835.3	TSL:3	c.442C>A	p.Pro148Thr	missense	Exon 5 of 5	ENSP00000358850.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:1

May 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.53
Sift	Benign	0.32	T
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.52		Loss of glycosylation at P183 (P = 0.0662)
MVP		0.98
MPC		1.0
ClinPred		0.73	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.51
Mutation Taster		=23/77	disease causing (ClinVar)

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: rs104894806; hg19: chrX-153609339;