X-154379493-C-G

Variant names:

• chrX-154379493-C-G
• rs781878601
• NM_000117.3:c.9C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_000117.3(EMD):​c.9C>G​(p.Asn3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,167,412 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N3N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., 1 hem., cov: 26)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10661006).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000264 (3/113634) while in subpopulation EAS AF = 0.000834 (3/3595). AF 95% confidence interval is 0.000227. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

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.9C>G	p.Asn3Lys	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.9C>G	p.Asn3Lys	missense	Exon 1 of 6	ENSP00000358857.4	P50402
	EMD	ENST00000933532.1		c.9C>G	p.Asn3Lys	missense	Exon 1 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.9C>G	p.Asn3Lys	missense	Exon 1 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 3 AN: 113585 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000831

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000874 AC: 1 AN: 114449 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.49e-7 AC: 1 AN: 1053778 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 344572

African (AFR) AF: 0.00 AC: 0 AN: 24825

American (AMR) AF: 0.00 AC: 0 AN: 28311

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18621

East Asian (EAS) AF: 0.0000368 AC: 1 AN: 27139

South Asian (SAS) AF: 0.00 AC: 0 AN: 50008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4055

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819650

Other (OTH) AF: 0.00 AC: 0 AN: 44315

GnomAD4 genome AF: 0.0000264 AC: 3 AN: 113634 Hom.: 0 Cov.: 26 AF XY: 0.0000279 AC XY: 1 AN XY: 35798

African (AFR) AF: 0.00 AC: 0 AN: 31452

American (AMR) AF: 0.00 AC: 0 AN: 10899

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.000834 AC: 3 AN: 3595

South Asian (SAS) AF: 0.00 AC: 0 AN: 2866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6367

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53343

Other (OTH) AF: 0.00 AC: 0 AN: 1554

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	Benign	0.30
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	19
DANN	Benign	0.61
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.079
Sift	Benign	0.047	D
Sift4G	Uncertain	0.017	D
Polyphen		0.0	B
Vest4		0.17
MutPred		0.49		Gain of ubiquitination at N3 (P = 0.0045)
MVP		0.33
MPC		0.35
ClinPred		0.045	T
GERP RS		3.1
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.32
gMVP		0.57
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs781878601; hg19: chrX-153607853;