chrX-21743749-C-C

Variant names:

• chrX-21743749-C-C
• NM_014332.3:c.

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_014332.3(SMPX):​c. variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMPX NM_014332.3 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.87
• Publications: 0 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: PanelApp Australia, 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 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.3258427 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.4, offset of 0 (no position change), new splice context is: gagGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPX	NM_014332.3	MANE Select	c.		splice_donor intron	N/A	NP_055147.1	Q9UHP9
	SMPX	NR_045617.2		n.		splice_donor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPX	ENST00000379494.4	TSL:1 MANE Select	c.		splice_donor intron	N/A	ENSP00000368808.3	Q9UHP9
	SMPX	ENST00000646008.1		c.		splice_donor intron	N/A	ENSP00000493671.1	Q9UHP9
	SMPX	ENST00000867835.1		c.		splice_donor intron	N/A	ENSP00000537894.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-21761867;