rs2239401

Variant names:

• chrX-630526-G-A
• rs2239401
• ENST00000381578.6:c.-372G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-630526-G-A
• chrX-630526-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000381578.6(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 ENST00000381578.6 5_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.0290
• Publications: 0 publications found

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]

SHOX Gene-Disease associations (from GenCC):

• Leri-Weill dyschondrosteosis

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Langer mesomelic dysplasia

  Inheritance: Unknown, XL, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• SHOX-related short stature

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381578.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	NM_006883.2		c.-372G>A		5_prime_UTR	Exon 2 of 6	NP_006874.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000381578.6	TSL:5	c.-372G>A		5_prime_UTR	Exon 2 of 6	ENSP00000370990.1
	SHOX	ENST00000334060.8	TSL:5	c.-372G>A		5_prime_UTR	Exon 2 of 6	ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31035 AN: 152002 Hom.: 3299 Cov.: 33

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

African (AFR) AF: 0.262 AC: 1992 AN: 7594

American (AMR) AF: 0.155 AC: 1416 AN: 9144

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 1429 AN: 7180

East Asian (EAS) AF: 0.166 AC: 2225 AN: 13420

South Asian (SAS) AF: 0.211 AC: 6835 AN: 32468

European-Finnish (FIN) AF: 0.124 AC: 1588 AN: 12800

Middle Eastern (MID) AF: 0.258 AC: 254 AN: 984

European-Non Finnish (NFE) AF: 0.177 AC: 25904 AN: 146274

Other (OTH) AF: 0.186 AC: 2522 AN: 13524

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

African (AFR) AF: 0.261 AC: 10831 AN: 41522

American (AMR) AF: 0.171 AC: 2606 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1019 AN: 5144

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4824

European-Finnish (FIN) AF: 0.142 AC: 1504 AN: 10604

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12471 AN: 67954

Other (OTH) AF: 0.216 AC: 457 AN: 2114

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

Mar 03, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.4
DANN	Benign	0.91
PhyloP100		-0.029
PromoterAI		0.052	Neutral

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

Other links and lift over

dbSNP: rs2239401; hg19: chrX-591261;