X-21737592-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_014332.3(SMPX):c.238C>G(p.Leu80Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMPX NM_014332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Small muscular protein (size 87) in uniprot entity SMPX_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_014332.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.238C>G	p.Leu80Val	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1	c.238C>G	p.Leu80Val	missense_variant	4/7
SMPX	XM_047441940.1	c.238C>G	p.Leu80Val	missense_variant	4/5
SMPX	NR_045617.2	n.425C>G		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.238C>G	p.Leu80Val	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.238C>G	p.Leu80Val	missense_variant	4/5			P1
SMPX	ENST00000494525.1	c.238C>G	p.Leu80Val	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Moderate, PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;D
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.081	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
Polyphen		1.0	D;D;D
Vest4		0.83
MutPred		0.18		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.57
MPC		0.43
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.91
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21755710;