X-21737569-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_014332.3(SMPX):c.261A>T(p.Glu87Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,093,358 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: SMPX NM_014332.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.151

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.24403733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.261A>T	p.Glu87Asp	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1	c.261A>T	p.Glu87Asp	missense_variant	4/7
SMPX	XM_047441940.1	c.261A>T	p.Glu87Asp	missense_variant	4/5
SMPX	NR_045617.2	n.448A>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.261A>T	p.Glu87Asp	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.261A>T	p.Glu87Asp	missense_variant	4/5			P1
SMPX	ENST00000494525.1	c.261A>T	p.Glu87Asp	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1093358 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 1 AN XY: 358934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.261A>T (p.E87D) alteration is located in exon 4 (coding exon 3) of the SMPX gene. This alteration results from a A to T substitution at nucleotide position 261, causing the glutamic acid (E) at amino acid position 87 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 22, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 87 of the SMPX protein (p.Glu87Asp). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2386251). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;T
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.80	D
PrimateAI	Uncertain	0.56	T
Polyphen		0.66	P;P;P
Vest4		0.17
MutPred		0.10		Loss of ubiquitination at K85 (P = 0.0787);Loss of ubiquitination at K85 (P = 0.0787);Loss of ubiquitination at K85 (P = 0.0787);
MVP		0.40
MPC		0.15
ClinPred		0.96	D
GERP RS		1.1
Varity_R		0.41
gMVP		0.27

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-21755687; COSMIC: COSV105315394;