rs397515752

Variant names:

• chrX-154381003-A-G
• rs397515752
• NM_000117.3:c.571A>G
• EMD p.Met191Val

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000117.3(EMD):​c.571A>G​(p.Met191Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M191I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.188
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• heart conduction disease

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

ACMG classification

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

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000117.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0512847).
• BP6: Variant X-154381003-A-G is Benign according to our data. Variant chrX-154381003-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42277.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	NM_000117.3	MANE Select	c.571A>G	p.Met191Val	missense	Exon 6 of 6	NP_000108.1	P50402

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	ENST00000369842.9	TSL:1 MANE Select	c.571A>G	p.Met191Val	missense	Exon 6 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.598A>G	p.Met200Val	missense	Exon 6 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.595A>G	p.Met199Val	missense	Exon 6 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098022 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363432

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000712 AC: 6 AN: 842111

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Emery-Dreifuss muscular dystrophy 1, X-linked (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	X-linked Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.19
DANN	Benign	0.33
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.19
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.16
Sift	Benign	0.48	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.21
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397515752;

hg19: chrX-153609363;