NM_000117.3:c.166G>A

Variant names:

• chrX-154379773-G-A
• rs1057520579
• NM_000117.3:c.166G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000117.3(EMD):​c.166G>A​(p.Ala56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,091,477 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 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. A56V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000028 (0 hom. 11 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.473
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• heart conduction disease

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.069049686).
• BP6: Variant X-154379773-G-A is Benign according to our data. Variant chrX-154379773-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379342.
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

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.166G>A	p.Ala56Thr	missense	Exon 2 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.166G>A	p.Ala56Thr	missense	Exon 2 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.166G>A	p.Ala56Thr	missense	Exon 2 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.166G>A	p.Ala56Thr	missense	Exon 2 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000178 AC: 3 AN: 168400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000406

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000284 AC: 31 AN: 1091477 Hom.: 0 Cov.: 30 AF XY: 0.0000307 AC XY: 11 AN XY: 358461

African (AFR) AF: 0.0000383 AC: 1 AN: 26104

American (AMR) AF: 0.00 AC: 0 AN: 34515

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19183

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.00 AC: 0 AN: 53512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.0000346 AC: 29 AN: 838968

Other (OTH) AF: 0.0000218 AC: 1 AN: 45814

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.47
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.13
Sift	Benign	0.10	T
Sift4G	Benign	0.087	T
Polyphen		0.27	B
Vest4		0.14
MutPred		0.060		Gain of glycosylation at A56 (P = 0.0105)
MVP		0.41
MPC		0.31
ClinPred		0.027	T
GERP RS		0.062
PromoterAI		0.045	Neutral
Varity_R		0.042
gMVP		0.34
Mutation Taster		=96/4	polymorphism

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: rs1057520579; hg19: chrX-153608133; COSMIC: COSV107475126; COSMIC: COSV107475126;