X-21737681-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_014332.3(SMPX):c.149C>T(p.Ser50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,208,620 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S50S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

SMPX
NM_014332.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Variant links:

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]

SMPX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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=0.09636921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMPX	NM_014332.3 linkuse as main transcript	c.149C>T	p.Ser50Leu	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1 linkuse as main transcript	c.149C>T	p.Ser50Leu	missense_variant	4/7
SMPX	XM_047441940.1 linkuse as main transcript	c.149C>T	p.Ser50Leu	missense_variant	4/5
SMPX	NR_045617.2 linkuse as main transcript	n.336C>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SMPX	ENST00000379494.4 linkuse as main transcript	c.149C>T	p.Ser50Leu	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1 linkuse as main transcript	c.149C>T	p.Ser50Leu	missense_variant	4/5			P1
SMPX	ENST00000494525.1 linkuse as main transcript	c.149C>T	p.Ser50Leu	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111874

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34054

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000945

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183099

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67663

show subpopulations

Gnomad AFR exome

AF:

0.000228

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1096746

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362190

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111874

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34054

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.0000945

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 50 of the SMPX protein (p.Ser50Leu). This variant is present in population databases (rs760877167, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SMPX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1983808). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.061

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.48

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T

FATHMM_MKL

Benign

0.51

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.096

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

Polyphen

0.049

B;B;B

Vest4

0.14

MVP

0.16

MPC

0.067

ClinPred

0.19

GERP RS

6.1

Varity_R

0.21

gMVP

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over