chrX-634734-C-A

Variant names:

• chrX-634734-C-A
• NM_000451.4:c.394C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000451.4(SHOX):​c.394C>A​(p.Leu132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,682 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom. 1 hem.)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96

Genes affected

SHOX (HGNC:10853): (SHOX homeobox) This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4	c.394C>A	p.Leu132Ile	missense_variant	Exon 2 of 5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.394C>A	p.Leu132Ile	missense_variant	Exon 3 of 6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.394C>A	p.Leu132Ile	missense_variant	Exon 2 of 5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.394C>A	p.Leu132Ile	missense_variant	Exon 2 of 5	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.394C>A	p.Leu132Ile	missense_variant	Exon 3 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.394C>A	p.Leu132Ile	missense_variant	Exon 3 of 6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460682 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;.
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H;H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.64
MutPred		0.86		Gain of catalytic residue at L132 (P = 0.0284);Gain of catalytic residue at L132 (P = 0.0284);Gain of catalytic residue at L132 (P = 0.0284);
MVP		0.94
MPC		1.5
ClinPred		1.0	D
GERP RS		-0.30
Varity_R		0.93

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-595469;