rs201681071

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_014332.3(SMPX):c.182A>G(p.Lys61Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,207,834 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. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000020 ( 0 hom. 5 hem. )

Consequence

SMPX
NM_014332.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.48

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 -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

BP4

Computational evidence support a benign effect (MetaRNN=0.1415802).

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMPX	NM_014332.3 linkuse as main transcript	c.182A>G	p.Lys61Arg	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1 linkuse as main transcript	c.182A>G	p.Lys61Arg	missense_variant	4/7
SMPX	XM_047441940.1 linkuse as main transcript	c.182A>G	p.Lys61Arg	missense_variant	4/5
SMPX	NR_045617.2 linkuse as main transcript	n.369A>G		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.182A>G	p.Lys61Arg	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1 linkuse as main transcript	c.182A>G	p.Lys61Arg	missense_variant	4/5			P1
SMPX	ENST00000494525.1 linkuse as main transcript	c.182A>G	p.Lys61Arg	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112345

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34495

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183294

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67784

show subpopulations

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:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1095489

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

360923

show subpopulations

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:

0.0000238

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112345

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34495

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 23, 2016

The p.Lys61Arg variant in SMPX has not been previously reported in individuals w ith hearing loss. This variant has been identified in 1/47913 European chromosom es by the Exome Aggregation Consortium, and the variant was reportedly in the he mizygous state (ExAC, http://exac.broadinstitute.org; dbSNP rs201681071). Comput ational prediction tools and conservation analyses suggest that the p.Lys61Arg v ariant may not impact the protein, though this information is not predictive eno ugh to rule out pathogenicity. In summary, the clinical significance of the p.Ly s61Arg variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2021

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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 229261). This variant has not been reported in the literature in individuals affected with SMPX-related conditions. This variant is present in population databases (rs201681071, ExAC 0.002%). This sequence change replaces lysine with arginine at codon 61 of the SMPX protein (p.Lys61Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.42

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.25

T;T;T

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.021

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

0.56

PrimateAI

Uncertain

0.58

Polyphen

0.0040

B;B;B

Vest4

0.24

MVP

0.27

MPC

0.39

ClinPred

0.85

GERP RS

6.1

Varity_R

0.15

gMVP

0.087

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