NM_000117.3:c.144C>G

Variant names:

• chrX-154379751-C-G
• rs200537612
• NM_000117.3:c.144C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000117.3(EMD):​c.144C>G​(p.Leu48Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,249 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L48L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: EMD NM_000117.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.89
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-154379751-C-G is Benign according to our data. Variant chrX-154379751-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 500783.
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.

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.144C>G	p.Leu48Leu	synonymous	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.144C>G	p.Leu48Leu	synonymous	Exon 2 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.144C>G	p.Leu48Leu	synonymous	Exon 2 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.144C>G	p.Leu48Leu	synonymous	Exon 2 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094249 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360737

African (AFR) AF: 0.00 AC: 0 AN: 26251

American (AMR) AF: 0.00 AC: 0 AN: 34710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19269

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 53659

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39243

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840944

Other (OTH) AF: 0.00 AC: 0 AN: 45932

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.64
PhyloP100		-2.9
PromoterAI		-0.049	Neutral

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

Other links and lift over

dbSNP: rs200537612; hg19: chrX-153608111;