X-21737616-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_014332.3(SMPX):c.214G>T(p.Glu72Ter) 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).

• 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

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.199 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• 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. Variant chrX-21737616-C-A is described in Lovd as [Pathogenic]. Variant chrX-21737616-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.214G>T	p.Glu72Ter	stop_gained	4/5	ENST00000379494.4
SMPX	XM_047441939.1	c.214G>T	p.Glu72Ter	stop_gained	4/7
SMPX	XM_047441940.1	c.214G>T	p.Glu72Ter	stop_gained	4/5
SMPX	NR_045617.2	n.401G>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.214G>T	p.Glu72Ter	stop_gained	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.214G>T	p.Glu72Ter	stop_gained	4/5			P1
SMPX	ENST00000494525.1	c.214G>T	p.Glu72Ter	stop_gained, NMD_transcript_variant	4/6	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

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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
MutationTaster	Benign	1.0	A
Vest4		0.41
GERP RS		6.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906708; hg19: chrX-21755734;