NM_014332.3:c.182A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_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. 12/19 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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, X-linked 4
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
myopathy, distal, 7, adult-onset, X-linked
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
X-linked nonsyndromic hearing loss
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

SMPX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 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

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.041672 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to myopathy, distal, 7, adult-onset, X-linked, nonsyndromic genetic hearing loss, X-linked nonsyndromic hearing loss, hearing loss, X-linked 4.

BP4

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

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPX	NM_014332.3 link	c.182A>G	p.Lys61Arg	missense_variant	Exon 4 of 5	ENST00000379494.4	NP_055147.1	Q9UHP9A0A024RBY1
SMPX	XM_047441939.1 link	c.182A>G	p.Lys61Arg	missense_variant	Exon 4 of 7		XP_047297895.1
SMPX	XM_047441940.1 link	c.182A>G	p.Lys61Arg	missense_variant	Exon 4 of 5		XP_047297896.1
SMPX	NR_045617.2 link	n.369A>G		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMPX	ENST00000379494.4 link	c.182A>G	p.Lys61Arg	missense_variant	Exon 4 of 5	1	NM_014332.3	ENSP00000368808.3	Q9UHP9
SMPX	ENST00000646008.1 link	c.182A>G	p.Lys61Arg	missense_variant	Exon 4 of 5			ENSP00000493671.1	Q9UHP9
SMPX	ENST00000494525.1 link	n.182A>G		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000495170.1	Q9UHP9

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112345

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183294

AF XY:

0.0000295

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 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

African (AFR)

AF:

0.00

AC:

AN:

26348

American (AMR)

AF:

0.00

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19362

East Asian (EAS)

AF:

0.00

AC:

AN:

30190

South Asian (SAS)

AF:

0.00

AC:

AN:

54080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000238

AC:

AN:

839645

Other (OTH)

AF:

0.0000435

AC:

AN:

46010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112345

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34495

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30866

American (AMR)

AF:

0.00

AC:

AN:

10629

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3582

South Asian (SAS)

AF:

0.00

AC:

AN:

2706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53293

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Jan 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;T;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

.;.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.97

PhyloP100

2.5

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.9

.;N;.

REVEL

Benign

0.099

Sift

Benign

0.52

.;T;.

Sift4G

Benign

0.78

.;T;.

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

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over