rs750375727

chrX-644455-C-AchrX-644455-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000451.4(SHOX):c.698C>A(p.Ala233Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000073 in 1,370,048 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A233V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom. 1 hem.)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Short stature homeobox protein (size 291) in uniprot entity SHOX_HUMAN there are 38 pathogenic changes around while only 6 benign (86%) in NM_000451.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.698C>A	p.Ala233Glu	missense_variant	5/5	ENST00000686671.1
SHOX	NM_006883.2	c.633+3368C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.698C>A	p.Ala233Glu	missense_variant	5/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.633+3368C>A		intron_variant		1
SHOX	ENST00000381578.6	c.698C>A	p.Ala233Glu	missense_variant	6/6	5		P1
SHOX	ENST00000334060.8	c.633+3368C>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000827 AC: 1 AN: 120878 Hom.: 0 AF XY: 0.0000151 AC XY: 1 AN XY: 66436

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 7.30e-7 AC: 1 AN: 1370048 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 676290

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: 0.00

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.035	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.57
Sift	Benign	0.044	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.27		Gain of catalytic residue at A233 (P = 0.0329);
MVP		0.94
MPC		1.7
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.59

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: rs750375727; hg19: chrX-605190;