X-21737633-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_014332.3(SMPX):c.197C>G(p.Pro66Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMPX NM_014332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 Likely_pathogenic. Variant got 6 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPX	NM_014332.3	c.197C>G	p.Pro66Arg	missense_variant	4/5	ENST00000379494.4
SMPX	XM_047441939.1	c.197C>G	p.Pro66Arg	missense_variant	4/7
SMPX	XM_047441940.1	c.197C>G	p.Pro66Arg	missense_variant	4/5
SMPX	NR_045617.2	n.384C>G		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPX	ENST00000379494.4	c.197C>G	p.Pro66Arg	missense_variant	4/5	1	NM_014332.3	P1
SMPX	ENST00000646008.1	c.197C>G	p.Pro66Arg	missense_variant	4/5			P1
SMPX	ENST00000494525.1	c.197C>G	p.Pro66Arg	missense_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hearing loss, X-linked 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.197C>Gp.Pro66Arg variant in SMPX gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. The amino acid Pro at position 66 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Pro66Arg in SMPX is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;D
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.098	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
Polyphen		1.0	D;D;D
Vest4		0.81
MutPred		0.31		Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);
MVP		0.65
MPC		0.45
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.93
gMVP		0.41

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-21755751;