X-21737603-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_014332.3(SMPX):c.227T>C(p.Ile76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000458 in 1,091,856 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: 0.0000046 (0 hom. 2 hem.)
• Consequence: SMPX NM_014332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40

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 1 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.2882865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.227T>C	p.Ile76Thr	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1	c.227T>C	p.Ile76Thr	missense_variant	4/7
SMPX	XM_047441940.1	c.227T>C	p.Ile76Thr	missense_variant	4/5
SMPX	NR_045617.2	n.414T>C		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.227T>C	p.Ile76Thr	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.227T>C	p.Ile76Thr	missense_variant	4/5			P1
SMPX	ENST00000494525.1	c.227T>C	p.Ile76Thr	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183285 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67783

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1091856 Hom.: 0 Cov.: 28 AF XY: 0.00000560 AC XY: 2 AN XY: 357366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000598

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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 11, 2021

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 76 of the SMPX protein (p.Ile76Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals affected with SMPX-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.89	D
PrimateAI	Uncertain	0.70	T
Polyphen		0.28	B;B;B
Vest4		0.57
MutPred		0.23		Loss of stability (P = 0.0112);Loss of stability (P = 0.0112);Loss of stability (P = 0.0112);
MVP		0.46
MPC		0.11
ClinPred		0.74	D
GERP RS		6.2
Varity_R		0.51
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs1472137937; hg19: chrX-21755721;