X-21743782-TG-TGG

Variant names:

• chrX-21743782-T-TG
• rs398122930
• NM_014332.3:c.99dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_014332.3(SMPX):​c.99dupC​(p.Arg34GlnfsTer8) 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
• Publications: 6 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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. There are 15 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 VariationId is 445653.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014332.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPX	NM_014332.3	MANE Select	c.99dupC	p.Arg34GlnfsTer8	frameshift	Exon 3 of 5	NP_055147.1
	SMPX	NR_045617.2		n.286dupC		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPX	ENST00000379494.4	TSL:1 MANE Select	c.99dupC	p.Arg34GlnfsTer8	frameshift	Exon 3 of 5	ENSP00000368808.3
	SMPX	ENST00000646008.1		c.99dupC	p.Arg34GlnfsTer8	frameshift	Exon 3 of 5	ENSP00000493671.1
	SMPX	ENST00000867835.1		c.99dupC	p.Arg34GlnfsTer8	frameshift	Exon 4 of 6	ENSP00000537894.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00 AC: 0 AN: 183081 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 26358

American (AMR) AF: 0.00 AC: 0 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840600

Other (OTH) AF: 0.00 AC: 0 AN: 46031

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70

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

Other links and lift over

dbSNP: rs398122930; hg19: chrX-21761900; COSMIC: COSV65277405;