X-21737657-G-A

Position:

• chrX-21737657-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014332.3(SMPX):​c.173C>T​(p.Pro58Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SMPX NM_014332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.173C>T	p.Pro58Leu	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1	c.173C>T	p.Pro58Leu	missense_variant	4/7
SMPX	XM_047441940.1	c.173C>T	p.Pro58Leu	missense_variant	4/5
SMPX	NR_045617.2	n.360C>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.173C>T	p.Pro58Leu	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.173C>T	p.Pro58Leu	missense_variant	4/5			P1
SMPX	ENST00000494525.1	c.173C>T	p.Pro58Leu	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2022

This variant has not been reported in the literature in individuals affected with SMPX-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 58 of the SMPX protein (p.Pro58Leu). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;D
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
Polyphen		0.94	P;P;P
Vest4		0.57
MutPred		0.11		Loss of glycosylation at K62 (P = 0.1885);Loss of glycosylation at K62 (P = 0.1885);Loss of glycosylation at K62 (P = 0.1885);
MVP		0.60
MPC		0.27
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.85
gMVP		0.37

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-21755775;