X-154381042-C-G

Variant names:

• chrX-154381042-C-G
• rs782299893
• NM_000117.3:c.610C>G

Variant summary

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

The NM_000117.3(EMD):​c.610C>G​(p.Arg204Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,098,070 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000032 (0 hom. 8 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.09
• Publications: 1 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=0.060557067).
• BP6: Variant X-154381042-C-G is Benign according to our data. Variant chrX-154381042-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286452.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000319 (35/1098070) while in subpopulation AMR AF = 0.000994 (35/35206). AF 95% confidence interval is 0.000734. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 8 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.610C>G	p.Arg204Gly	missense	Exon 6 of 6	NP_000108.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	ENST00000369842.9	TSL:1 MANE Select	c.610C>G	p.Arg204Gly	missense	Exon 6 of 6	ENSP00000358857.4
	EMD	ENST00000933532.1		c.637C>G	p.Arg213Gly	missense	Exon 6 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.634C>G	p.Arg212Gly	missense	Exon 6 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.000153 AC: 28 AN: 183163 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000319 AC: 35 AN: 1098070 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 8 AN XY: 363492

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.000994 AC: 35 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842133

Other (OTH) AF: 0.00 AC: 0 AN: 46091

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000181 AC: 22

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Emery-Dreifuss muscular dystrophy 1, X-linked (1)
-	-	1	X-linked Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.79	P
Vest4		0.35
MutPred		0.41		Loss of MoRF binding (P = 0.0348)
MVP		0.84
MPC		0.61
ClinPred		0.15	T
GERP RS		2.0
Varity_R		0.22
gMVP		0.66
Mutation Taster		=95/5	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: rs782299893; hg19: chrX-153609402;