Variant X-21737618-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_014332.3(SMPX):c.212C>T(p.Ser71Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000748 in 1,202,855 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 3 hem. )

Consequence

SMPX
NM_014332.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.90

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 Likely_benign. 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.792

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMPX	NM_014332.3 linkuse as main transcript	c.212C>T	p.Ser71Leu	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1 linkuse as main transcript	c.212C>T	p.Ser71Leu	missense_variant	4/7
SMPX	XM_047441940.1 linkuse as main transcript	c.212C>T	p.Ser71Leu	missense_variant	4/5
SMPX	NR_045617.2 linkuse as main transcript	n.399C>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.212C>T	p.Ser71Leu	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1 linkuse as main transcript	c.212C>T	p.Ser71Leu	missense_variant	4/5			P1
SMPX	ENST00000494525.1 linkuse as main transcript	c.212C>T	p.Ser71Leu	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111759

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

33965

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183289

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67787

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000458

AC:

AN:

1091041

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

356633

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000663

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111814

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

34030

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

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

Apr 23, 2022

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 71 of the SMPX protein (p.Ser71Leu). This variant is present in population databases (rs200892029, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SMPX-related conditions. 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"). 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

0.23

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;D;D

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Uncertain

0.092

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

Polyphen

1.0

D;D;D

Vest4

0.53

MVP

0.62

MPC

0.067

ClinPred

0.88

GERP RS

6.1

Varity_R

0.80

gMVP

0.49

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