rs387906708

Variant names:

• chrX-21737616-C-A
• rs387906708
• NM_014332.3:c.214G>T

Variant summary

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

The NM_014332.3(SMPX):​c.214G>T​(p.Glu72*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMPX NM_014332.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.08
• Publications: 5 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-21737616-C-A is Pathogenic according to our data. Variant chrX-21737616-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 29947.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.214G>T	p.Glu72*	stop_gained	Exon 4 of 5	ENST00000379494.4	NP_055147.1
SMPX	XM_047441939.1	c.214G>T	p.Glu72*	stop_gained	Exon 4 of 7		XP_047297895.1
SMPX	XM_047441940.1	c.214G>T	p.Glu72*	stop_gained	Exon 4 of 5		XP_047297896.1
SMPX	NR_045617.2	n.401G>T		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPX	ENST00000379494.4	c.214G>T	p.Glu72*	stop_gained	Exon 4 of 5	1	NM_014332.3	ENSP00000368808.3
SMPX	ENST00000646008.1	c.214G>T	p.Glu72*	stop_gained	Exon 4 of 5			ENSP00000493671.1
SMPX	ENST00000494525.1	n.214G>T		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000495170.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		6.1
Vest4		0.41
GERP RS		6.1
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387906708; hg19: chrX-21755734;