X-154380781-C-T

Variant names:

• chrX-154380781-C-T
• rs139983160
• NM_000117.3:c.428C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000369842.9(EMD):​c.428C>T​(p.Ser143Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,210,717 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 86 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).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.00018 (0 hom. 80 hem.)
• Consequence: EMD ENST00000369842.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: -0.00400
• Publications: 5 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• heart conduction disease

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013234675).
• BP6: Variant X-154380781-C-T is Benign according to our data. Variant chrX-154380781-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237013.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000213 (24/112632) while in subpopulation NFE AF = 0.000226 (12/53166). AF 95% confidence interval is 0.00013. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000369842.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	NM_000117.3	MANE Select	c.428C>T	p.Ser143Phe	missense	Exon 5 of 6	NP_000108.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	ENST00000369842.9	TSL:1 MANE Select	c.428C>T	p.Ser143Phe	missense	Exon 5 of 6	ENSP00000358857.4
	EMD	ENST00000683627.1		c.428C>T	p.Ser143Phe	missense	Exon 5 of 7	ENSP00000507533.1
	EMD	ENST00000369835.3	TSL:3	c.323C>T	p.Ser108Phe	missense	Exon 4 of 5	ENSP00000358850.3

Frequencies

GnomAD3 genomes AF: 0.000213 AC: 24 AN: 112579 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0148

Gnomad AMR AF: 0.000186

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: 0.000226

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000207 AC: 38 AN: 183290 AF XY: 0.000265

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: 0.000440

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000180 AC: 198 AN: 1098085 Hom.: 0 Cov.: 32 AF XY: 0.000220 AC XY: 80 AN XY: 363507

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19386

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

South Asian (SAS) AF: 0.0000923 AC: 5 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40382

Middle Eastern (MID) AF: 0.00146 AC: 6 AN: 4122

European-Non Finnish (NFE) AF: 0.000213 AC: 179 AN: 842142

Other (OTH) AF: 0.000152 AC: 7 AN: 46092

GnomAD4 genome AF: 0.000213 AC: 24 AN: 112632 Hom.: 0 Cov.: 24 AF XY: 0.000172 AC XY: 6 AN XY: 34796

African (AFR) AF: 0.00 AC: 0 AN: 31068

American (AMR) AF: 0.000186 AC: 2 AN: 10772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6249

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53166

Other (OTH) AF: 0.00 AC: 0 AN: 1534

Alfa AF: 0.000267 Hom.: 12

Bravo AF: 0.000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000981

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	not specified (2)
-	-	2	X-linked Emery-Dreifuss muscular dystrophy (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.0040
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.029	D
Sift4G	Benign	0.064	T
Polyphen		0.72	P
Vest4		0.28
MVP		0.71
MPC		0.67
ClinPred		0.050	T
GERP RS		0.46
Varity_R		0.12
gMVP		0.30
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs139983160; hg19: chrX-153609141;