rs1557182198

Variant names:

• chrX-154379529-GCTGCGCCGGTACAACATCCCGCACGGGCCTGTAGTAGGTACGC-G
• rs1557182198
• NM_000117.3:c.46_82+6delCTGCGCCGGTACAACATCCCGCACGGGCCTGTAGTAGGTACGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000117.3(EMD):​c.46_82+6delCTGCGCCGGTACAACATCCCGCACGGGCCTGTAGTAGGTACGC​(p.Leu16ValfsTer34) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L16L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: EMD NM_000117.3 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.05
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 82 pathogenic variants in the truncated region.
• PP5: Variant X-154379529-GCTGCGCCGGTACAACATCCCGCACGGGCCTGTAGTAGGTACGC-G is Pathogenic according to our data. Variant chrX-154379529-GCTGCGCCGGTACAACATCCCGCACGGGCCTGTAGTAGGTACGC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433168.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.46_82+6delCTGCGCCGGTACAACATCCCGCACGGGCCTGTAGTAGGTACGC	p.Leu16ValfsTer34	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.46_82+6delCTGCGCCGGTACAACATCCCGCACGGGCCTGTAGTAGGTACGC	p.Leu16ValfsTer34	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes Cov.: 25

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 25

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 14, 2016

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

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

Other links and lift over

dbSNP: rs1557182198; hg19: chrX-153607889;