X-21743782-TG-TGG

Position:

• chrX-21743782-TG-TGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_014332.3(SMPX):​c.99dupC​(p.Arg34fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,498 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SMPX NM_014332.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.703

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.629 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-21743782-T-TG is Pathogenic according to our data. Variant chrX-21743782-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 445653.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPX	NM_014332.3	c.99dupC	p.Arg34fs	frameshift_variant	3/5	ENST00000379494.4	NP_055147.1
SMPX	XM_047441939.1	c.99dupC	p.Arg34fs	frameshift_variant	3/7		XP_047297895.1
SMPX	XM_047441940.1	c.99dupC	p.Arg34fs	frameshift_variant	3/5		XP_047297896.1
SMPX	NR_045617.2	n.286dupC		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPX	ENST00000379494.4	c.99dupC	p.Arg34fs	frameshift_variant	3/5	1	NM_014332.3	ENSP00000368808.3
SMPX	ENST00000646008.1	c.99dupC	p.Arg34fs	frameshift_variant	3/5			ENSP00000493671.1
SMPX	ENST00000494525.1	n.99dupC		non_coding_transcript_exon_variant	3/6	5		ENSP00000495170.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096498 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362010

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs398122930; hg19: chrX-21761900;