rs2239401

Positions:

• chrX-630526-G-A
• chrX-630526-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006883.2(SHOX):​c.-372G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 395,508 control chromosomes in the GnomAD database, including 7,691 homozygotes. There are 38,515 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.20 (3302 hom., 15093 hem., cov: 33)
  • Exomes 𝑓: 0.18 (4389 hom. 23422 hem.)
• Consequence: SHOX NM_006883.2 5_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.0290

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOX	NM_006883.2	c.-372G>A		5_prime_UTR_variant	2/6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000334060.8	c.-372G>A		5_prime_UTR_variant	2/6	5		ENSP00000335505
SHOX	ENST00000381578.6	c.-372G>A		5_prime_UTR_variant	2/6	5		ENSP00000370990	P1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31035 AN: 152002 Hom.: 3299 Cov.: 33 AF XY: 0.203 AC XY: 15064 AN XY: 74246

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.181 AC: 44165 AN: 243388 Hom.: 4389 Cov.: 0 AF XY: 0.184 AC XY: 23422 AN XY: 127400

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.204 AC: 31057 AN: 152120 Hom.: 3302 Cov.: 33 AF XY: 0.203 AC XY: 15093 AN XY: 74374

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.216

Bravo AF: 0.209

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SHOX-related short stature Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Human Genetics Disease in Children – Taif University, Taif University

Mar 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.4
DANN	Benign	0.91

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: rs2239401; hg19: chrX-591261;