rs398122848

Variant names:

• chrX-21743751-TC-T
• rs398122848
• NM_014332.3:c.130delG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_014332.3(SMPX):​c.130delG​(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
• Publications: 4 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: Pathogenic. The variant received 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 VariationId is 29948.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.130delG	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	Exon 3 of 5	ENST00000379494.4	NP_055147.1
SMPX	XM_047441939.1	c.130delG	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	Exon 3 of 7		XP_047297895.1
SMPX	XM_047441940.1	c.130delG	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	Exon 3 of 5		XP_047297896.1
SMPX	NR_045617.2	n.317delG		splice_region_variant, 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.130delG	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	Exon 3 of 5	1	NM_014332.3	ENSP00000368808.3
SMPX	ENST00000646008.1	c.130delG	p.Glu44ArgfsTer37	frameshift_variant, splice_region_variant	Exon 3 of 5			ENSP00000493671.1
SMPX	ENST00000494525.1	n.130delG		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000495170.1

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

May 13, 2011

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		4.2
Mutation Taster		=8/192	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: rs398122848; hg19: chrX-21761869;