rs781878601

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-154379493-C-G
• chrX-154379493-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

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 -3 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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;