rs398122848

chrX-21743751-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_014332.3(SMPX):c.130del(p.Glu44ArgfsTer37) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E44E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMPX NM_014332.3 frameshift, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.17

Genes affected

SMPX (HGNC:11122): (small muscle protein X-linked) This gene encodes a small protein that has no known functional domains. Mutations in this gene are a cause of X-linked deafness-4, and the encoded protein may play a role in the maintenance of inner ear cells subjected to mechanical stress. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-21743751-TC-T is Pathogenic according to our data. Variant chrX-21743751-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 29948.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-21743751-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.130del	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	3/5	ENST00000379494.4
SMPX	XM_047441939.1	c.130del	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	3/7
SMPX	XM_047441940.1	c.130del	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	3/5
SMPX	NR_045617.2	n.317del		splice_region_variant, non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.130del	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	3/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.130del	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	3/5			P1
SMPX	ENST00000494525.1	c.130del	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant, NMD_transcript_variant	3/6	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hearing loss, X-linked 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 13, 2011

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122848; hg19: chrX-21761869;