X-154379751-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000117.3(EMD):​c.144C>T​(p.Leu48Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,206,085 control chromosomes in the GnomAD database, including 1 homozygotes. There are 183 hemizygotes 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 Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., 101 hem., cov: 25)
  • Exomes 𝑓: 0.00030 (0 hom. 82 hem.)
• Consequence: EMD NM_000117.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-154379751-C-T is Benign according to our data. Variant chrX-154379751-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42271.
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00293 (328/111838) while in subpopulation AFR AF = 0.0097 (299/30840). AF 95% confidence interval is 0.00879. There are 1 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 101 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.144C>T	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>T	p.Leu48Leu	synonymous	Exon 2 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.144C>T	p.Leu48Leu	synonymous	Exon 2 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.144C>T	p.Leu48Leu	synonymous	Exon 2 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 325 AN: 111788 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.00962

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00253

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.000666

GnomAD2 exomes AF: 0.000810 AC: 138 AN: 170307 AF XY: 0.000483

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000475

GnomAD4 exome AF: 0.000304 AC: 333 AN: 1094247 Hom.: 0 Cov.: 31 AF XY: 0.000227 AC XY: 82 AN XY: 360737

African (AFR) AF: 0.0102 AC: 267 AN: 26249

American (AMR) AF: 0.000519 AC: 18 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: 0.0000186 AC: 1 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: 0.00000476 AC: 4 AN: 840944

Other (OTH) AF: 0.000936 AC: 43 AN: 45932

GnomAD4 genome AF: 0.00293 AC: 328 AN: 111838 Hom.: 1 Cov.: 25 AF XY: 0.00297 AC XY: 101 AN XY: 34022

African (AFR) AF: 0.00970 AC: 299 AN: 30840

American (AMR) AF: 0.00253 AC: 27 AN: 10681

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52967

Other (OTH) AF: 0.000657 AC: 1 AN: 1521

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.00362

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	X-linked Emery-Dreifuss muscular dystrophy (2)
-	1	-	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	EMD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.92
PhyloP100		-2.9
PromoterAI		0.042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs200537612; hg19: chrX-153608111;