rs199907508

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_014332.3(SMPX):c.132G>A(p.Glu44Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000631 in 1,198,986 control chromosomes in the GnomAD database, including 1 homozygotes. There are 235 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., 18 hem., cov: 23)

Exomes 𝑓: 0.00064 ( 1 hom. 217 hem. )

Consequence

SMPX
NM_014332.3 splice_region, synonymous

Scores

Splicing: ADA: 0.9990

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 5.87

Publications

2 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: Benign. The variant received -8 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant X-21743750-C-T is Benign according to our data. Variant chrX-21743750-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368152.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00052 (58/111466) while in subpopulation NFE AF = 0.000924 (49/53055). AF 95% confidence interval is 0.000717. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMPX	NM_014332.3 link	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5	ENST00000379494.4	NP_055147.1
SMPX	XM_047441939.1 link	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 7		XP_047297895.1
SMPX	XM_047441940.1 link	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5		XP_047297896.1
SMPX	NR_045617.2 link	n.319G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMPX	ENST00000379494.4 link	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5	1	NM_014332.3	ENSP00000368808.3
SMPX	ENST00000646008.1 link	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5			ENSP00000493671.1
SMPX	ENST00000494525.1 link	n.132G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000495170.1

Frequencies

GnomAD3 genomes

AF:

0.000521

AC:

AN:

111412

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000386

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000923

Gnomad OTH

AF:

0.000671

GnomAD2 exomes

AF:

0.000399

AC:

AN:

183007

AF XY:

0.000340

show subpopulations

Gnomad AFR exome

AF:

0.000152

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:

0.000846

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000642

AC:

698

AN:

1087520

Hom.:

Cov.:

AF XY:

0.000613

AC XY:

217

AN XY:

353784

show subpopulations

African (AFR)

AF:

0.000153

AC:

AN:

26210

American (AMR)

AF:

0.00

AC:

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19323

East Asian (EAS)

AF:

0.00

AC:

AN:

30159

South Asian (SAS)

AF:

0.00

AC:

AN:

53915

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4088

European-Non Finnish (NFE)

AF:

0.000808

AC:

673

AN:

832409

Other (OTH)

AF:

0.000437

AC:

AN:

45729

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000520

AC:

AN:

111466

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

AN XY:

33662

show subpopulations

African (AFR)

AF:

0.000195

AC:

AN:

30720

American (AMR)

AF:

0.00

AC:

AN:

10489

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3530

South Asian (SAS)

AF:

0.000387

AC:

AN:

2586

European-Finnish (FIN)

AF:

0.000166

AC:

AN:

6042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000924

AC:

AN:

53055

Other (OTH)

AF:

0.000662

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000746

Hom.:

Bravo

AF:

0.000480

EpiCase

AF:

0.000437

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 18, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Non-canonical splice site variant at the last nucleotide of exon 3 predicted to destroy the natural splice donor site to result in an in-frame deletion of exon 3; This variant is associated with the following publications: (PMID: 26969326, 28000701, 24123792) -

SMPX-related disorder

Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hearing loss, X-linked 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

5.9

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.69

Position offset: 0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over