X-154379496-C-T

Variant names:

• chrX-154379496-C-T
• rs782011714
• NM_000117.3:c.12C>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.12C>T​(p.Tyr4Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 1,168,059 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 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).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 26)
  • Exomes 𝑓: 0.000042 (0 hom. 16 hem.)
• Consequence: EMD NM_000117.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.796
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-154379496-C-T is Benign according to our data. Variant chrX-154379496-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290626.
• BP7: Synonymous conserved (PhyloP=0.796 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000616 (7/113652) while in subpopulation AFR AF = 0.000191 (6/31431). AF 95% confidence interval is 0.0000823. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 3 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.12C>T	p.Tyr4Tyr	synonymous	Exon 1 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.12C>T	p.Tyr4Tyr	synonymous	Exon 1 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.12C>T	p.Tyr4Tyr	synonymous	Exon 1 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.12C>T	p.Tyr4Tyr	synonymous	Exon 1 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 6 AN: 113604 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000187

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000173 AC: 2 AN: 115306 AF XY: 0.0000253

Gnomad AFR exome AF: 0.000139

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: 0.0000228

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 44 AN: 1054407 Hom.: 0 Cov.: 31 AF XY: 0.0000464 AC XY: 16 AN XY: 344827

African (AFR) AF: 0.0000804 AC: 2 AN: 24869

American (AMR) AF: 0.00 AC: 0 AN: 28420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18632

East Asian (EAS) AF: 0.00 AC: 0 AN: 27178

South Asian (SAS) AF: 0.00 AC: 0 AN: 50055

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4058

European-Non Finnish (NFE) AF: 0.0000488 AC: 40 AN: 819957

Other (OTH) AF: 0.0000451 AC: 2 AN: 44348

GnomAD4 genome AF: 0.0000616 AC: 7 AN: 113652 Hom.: 0 Cov.: 26 AF XY: 0.0000838 AC XY: 3 AN XY: 35806

African (AFR) AF: 0.000191 AC: 6 AN: 31431

American (AMR) AF: 0.00 AC: 0 AN: 10905

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3598

South Asian (SAS) AF: 0.00 AC: 0 AN: 2873

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53362

Other (OTH) AF: 0.00 AC: 0 AN: 1555

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.9
DANN	Benign	0.87
PhyloP100		0.80
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=99/1	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: rs782011714; hg19: chrX-153607856;