X-154379688-A-G

Variant names:

• chrX-154379688-A-G
• rs727504901
• NM_000117.3:c.83-2A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000117.3(EMD):​c.83-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: EMD NM_000117.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.21
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• heart conduction disease

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13725491 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154379688-A-G is Pathogenic according to our data. Variant chrX-154379688-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 179496.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3	c.83-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 5	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.83-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 5	1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000435 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuromuscular disease Pathogenic:1

Feb 17, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 83-2A>G variant in EMD has been reported in 1 individual with X-linked Emery -Dreifuss muscular dystrophy (Astejada 2007), and was not identified in large po pulation studies. A different variant at this same position (83-2A>C) was report ed in 1 individual with Emery-Dreifuss muscular dystrophy, suggesting that a cha nge at this position might not be tolerated (Bione 1995). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicte d to cause altered splicing leading to an abnormal or absent protein. In summary , this variant is likely to be pathogenic, though additional studies are require d to fully establish its clinical significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	31
DANN	Benign	0.76
FATHMM_MKL	Benign	0.71	D
PhyloP100		1.2
GERP RS		2.6
PromoterAI		0.022	Neutral
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: 15
DS_AL_spliceai		0.94		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504901; hg19: chrX-153608048;