rs199907508

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BS1BS2

The NM_014332.3(SMPX):c.132G>A(p.Glu44=) 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. 2/2 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

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 Benign. Variant got -7 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

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 male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMPX	NM_014332.3 linkuse as main transcript	c.132G>A	p.Glu44=	splice_region_variant, synonymous_variant	3/5	ENST00000379494.4
SMPX	XM_047441939.1 linkuse as main transcript	c.132G>A	p.Glu44=	splice_region_variant, synonymous_variant	3/7
SMPX	XM_047441940.1 linkuse as main transcript	c.132G>A	p.Glu44=	splice_region_variant, synonymous_variant	3/5
SMPX	NR_045617.2 linkuse as main transcript	n.319G>A		splice_region_variant, non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SMPX	ENST00000379494.4 linkuse as main transcript	c.132G>A	p.Glu44=	splice_region_variant, synonymous_variant	3/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1 linkuse as main transcript	c.132G>A	p.Glu44=	splice_region_variant, synonymous_variant	3/5			P1
SMPX	ENST00000494525.1 linkuse as main transcript	c.132G>A	p.Glu44=	splice_region_variant, synonymous_variant, NMD_transcript_variant	3/6	5

Frequencies

GnomAD3 genomes

AF:

0.000521

AC:

AN:

111412

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

AN XY:

33598

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

GnomAD3 exomes

AF:

0.000399

AC:

AN:

183007

Hom.:

AF XY:

0.000340

AC XY:

AN XY:

67595

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 SAS exome

AF:

0.0000524

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

Gnomad4 AFR exome

AF:

0.000153

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:

0.0000247

Gnomad4 NFE exome

AF:

0.000808

Gnomad4 OTH exome

AF:

0.000437

GnomAD4 genome

AF:

0.000520

AC:

AN:

111466

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

AN XY:

33662

show subpopulations

Gnomad4 AFR

AF:

0.000195

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000387

Gnomad4 FIN

AF:

0.000166

Gnomad4 NFE

AF:

0.000924

Gnomad4 OTH

AF:

0.000662

Alfa

AF:

0.000798

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2023	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: 24123792, 26969326, 28000701) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	- -

SMPX-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Dann

Benign

0.91

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

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