rs199907508

Variant names:

• chrX-21743750-C-T
• rs199907508
• NM_014332.3:c.132G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BS1 BS2

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:1 B:4
• Conservation: PhyloP100: 5.87

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. 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. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPX	NM_014332.3	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5	ENST00000379494.4	NP_055147.1
SMPX	XM_047441939.1	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 7		XP_047297895.1
SMPX	XM_047441940.1	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5		XP_047297896.1
SMPX	NR_045617.2	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	Appris	UniProt
SMPX	ENST00000379494.4	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5	1	NM_014332.3	ENSP00000368808.3
SMPX	ENST00000646008.1	c.132G>A	p.Glu44Glu	splice_region_variant, synonymous_variant	Exon 3 of 5			ENSP00000493671.1
SMPX	ENST00000494525.1	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: 58 AN: 111412 Hom.: 0 Cov.: 23 AF XY: 0.000536 AC XY: 18 AN XY: 33598

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: 73 AN: 183007 Hom.: 0 AF XY: 0.000340 AC XY: 23 AN XY: 67595

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.: 1 Cov.: 28 AF XY: 0.000613 AC XY: 217 AN XY: 353784

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: 58 AN: 111466 Hom.: 0 Cov.: 23 AF XY: 0.000535 AC XY: 18 AN XY: 33662

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.: 30

Bravo AF: 0.000480

EpiCase AF: 0.000437

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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

- -

Mar 10, 2024

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	20
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

Other links and lift over

dbSNP: rs199907508; hg19: chrX-21761868;