rs398122930

Variant names:

• chrX-21743782-TG-T
• rs398122930
• NM_014332.3:c.99delC

Your query was ambiguous. Multiple possible variants found:

• chrX-21743782-TG-T
• chrX-21743782-TG-TGG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_014332.3(SMPX):​c.99delC​(p.Arg34GlufsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMPX NM_014332.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.703
• Publications: 6 publications found

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]

SMPX Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, X-linked 4

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• myopathy, distal, 7, adult-onset, X-linked

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• X-linked nonsyndromic hearing loss

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-21743782-TG-T is Pathogenic according to our data. Variant chrX-21743782-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 40063.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPX	NM_014332.3	c.99delC	p.Arg34GlufsTer47	frameshift_variant	Exon 3 of 5	ENST00000379494.4	NP_055147.1
SMPX	XM_047441939.1	c.99delC	p.Arg34GlufsTer47	frameshift_variant	Exon 3 of 7		XP_047297895.1
SMPX	XM_047441940.1	c.99delC	p.Arg34GlufsTer47	frameshift_variant	Exon 3 of 5		XP_047297896.1
SMPX	NR_045617.2	n.286delC		non_coding_transcript_exon_variant	Exon 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPX	ENST00000379494.4	c.99delC	p.Arg34GlufsTer47	frameshift_variant	Exon 3 of 5	1	NM_014332.3	ENSP00000368808.3
SMPX	ENST00000646008.1	c.99delC	p.Arg34GlufsTer47	frameshift_variant	Exon 3 of 5			ENSP00000493671.1
SMPX	ENST00000494525.1	n.99delC		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000495170.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1096493 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362007

African (AFR) AF: 0.00 AC: 0 AN: 26358

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840596

Other (OTH) AF: 0.00 AC: 0 AN: 46031

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hearing loss, X-linked 4 Pathogenic:1

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70
Mutation Taster		=32/168	disease causing (ClinVar)

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: rs398122930; hg19: chrX-21761900; COSMIC: COSV65277115;