X-154379507-C-T

Variant names:

• chrX-154379507-C-T
• rs869025400
• NM_000117.3:c.23C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000117.3(EMD):​c.23C>T​(p.Ser8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,055,755 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S8W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000019 (0 hom. 2 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.913
• 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity EMD_HUMAN
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.23C>T	p.Ser8Leu	missense	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.23C>T	p.Ser8Leu	missense	Exon 1 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.23C>T	p.Ser8Leu	missense	Exon 1 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.23C>T	p.Ser8Leu	missense	Exon 1 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000189 AC: 2 AN: 1055755 Hom.: 0 Cov.: 31 AF XY: 0.00000579 AC XY: 2 AN XY: 345175

African (AFR) AF: 0.00 AC: 0 AN: 24959

American (AMR) AF: 0.00 AC: 0 AN: 28665

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18649

East Asian (EAS) AF: 0.00 AC: 0 AN: 27277

South Asian (SAS) AF: 0.00 AC: 0 AN: 50139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36931

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4063

European-Non Finnish (NFE) AF: 0.00000244 AC: 2 AN: 820652

Other (OTH) AF: 0.00 AC: 0 AN: 44420

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Benign	0.84
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.91
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.68		Loss of disorder (P = 0.0227)
MVP		0.90
MPC		0.90
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		-0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.85
Mutation Taster		=77/23	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: rs869025400; hg19: chrX-153607867;