X-21737597-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP5_Moderate

The NM_014332.3(SMPX):c.233G>A(p.Ser78Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,093,412 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: SMPX NM_014332.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.08

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 Uncertain_significance. 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
• PP5: Variant X-21737597-C-T is Pathogenic according to our data. Variant chrX-21737597-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1451817.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.233G>A	p.Ser78Asn	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1	c.233G>A	p.Ser78Asn	missense_variant	4/7
SMPX	XM_047441940.1	c.233G>A	p.Ser78Asn	missense_variant	4/5
SMPX	NR_045617.2	n.420G>A		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.233G>A	p.Ser78Asn	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.233G>A	p.Ser78Asn	missense_variant	4/5			P1
SMPX	ENST00000494525.1	c.233G>A	p.Ser78Asn	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1093412 Hom.: 0 Cov.: 28 AF XY: 0.00000557 AC XY: 2 AN XY: 358926

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: 0.00000358

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, distal, 7, adult-onset, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 13, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 78 of the SMPX protein (p.Ser78Asn). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SMPX function (PMID: 33974137). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1451817). This missense change has been observed in individuals with distal myopathy (PMID: 33974137). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;D
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.075	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
Polyphen		0.99	D;D;D
Vest4		0.86
MutPred		0.17		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.31
MPC		0.41
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21755715;