rs368661339

Variant names:

• chrX-154380969-G-A
• rs368661339
• NM_000117.3:c.537G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000117.3(EMD):​c.537G>A​(p.Leu179Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,209,445 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 48 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. L179L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 7 hem., cov: 24)
  • Exomes 𝑓: 0.00011 (0 hom. 41 hem.)
• Consequence: EMD NM_000117.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0380
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-154380969-G-A is Benign according to our data. Variant chrX-154380969-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447314.
• BP7: Synonymous conserved (PhyloP=-0.038 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 7 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.537G>A	p.Leu179Leu	synonymous	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.537G>A	p.Leu179Leu	synonymous	Exon 6 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.564G>A	p.Leu188Leu	synonymous	Exon 6 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.561G>A	p.Leu187Leu	synonymous	Exon 6 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 16 AN: 111503 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00566

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: 0.00

GnomAD2 exomes AF: 0.000295 AC: 54 AN: 182929 AF XY: 0.000311

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00683

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000115 AC: 126 AN: 1097942 Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 41 AN XY: 363360

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00552 AC: 107 AN: 19386

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 842137

Other (OTH) AF: 0.000174 AC: 8 AN: 46092

GnomAD4 genome AF: 0.000143 AC: 16 AN: 111503 Hom.: 0 Cov.: 24 AF XY: 0.000208 AC XY: 7 AN XY: 33703

African (AFR) AF: 0.00 AC: 0 AN: 30598

American (AMR) AF: 0.00 AC: 0 AN: 10626

Ashkenazi Jewish (ASJ) AF: 0.00566 AC: 15 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52939

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.000955 Hom.: 4

Bravo AF: 0.000147

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Emery-Dreifuss muscular dystrophy (1)
-	-	1	not specified (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	1.4
DANN	Benign	0.50
PhyloP100		-0.038
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs368661339; hg19: chrX-153609329;