rs28474801

chrX-658808-G-AchrX-658808-G-CchrX-658808-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000381575.6(SHOX):c.657G>A(p.Pro219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 384,448 control chromosomes in the GnomAD database, including 83,240 homozygotes. There are 135,716 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37556 hom., 50134 hem., cov: 23)
  • Exomes 𝑓: 0.61 (45684 hom. 85582 hem.)
• Consequence: SHOX ENST00000381575.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.07

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-658808-G-A is Benign according to our data. Variant chrX-658808-G-A is described in ClinVar as [Benign]. Clinvar id is 586580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_006883.2	c.657G>A	p.Pro219=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000381575.6	c.657G>A	p.Pro219=	synonymous_variant	5/5	1
SHOX	ENST00000334060.8	c.657G>A	p.Pro219=	synonymous_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.704 AC: 103690 AN: 147328 Hom.: 37509 Cov.: 23 AF XY: 0.701 AC XY: 50024 AN XY: 71392

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.676

GnomAD3 exomes AF: 0.602 AC: 56209 AN: 93302 Hom.: 17686 AF XY: 0.609 AC XY: 31420 AN XY: 51606

Gnomad AFR exome AF: 0.857

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.660

Gnomad SAS exome AF: 0.661

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.581

GnomAD4 exome AF: 0.612 AC: 145133 AN: 237004 Hom.: 45684 Cov.: 0 AF XY: 0.622 AC XY: 85582 AN XY: 137582

Gnomad4 AFR exome AF: 0.866

Gnomad4 AMR exome AF: 0.554

Gnomad4 ASJ exome AF: 0.541

Gnomad4 EAS exome AF: 0.683

Gnomad4 SAS exome AF: 0.674

Gnomad4 FIN exome AF: 0.540

Gnomad4 NFE exome AF: 0.595

Gnomad4 OTH exome AF: 0.620

GnomAD4 genome AF: 0.704 AC: 103795 AN: 147444 Hom.: 37556 Cov.: 23 AF XY: 0.701 AC XY: 50134 AN XY: 71512

Gnomad4 AFR AF: 0.892

Gnomad4 AMR AF: 0.630

Gnomad4 ASJ AF: 0.574

Gnomad4 EAS AF: 0.734

Gnomad4 SAS AF: 0.696

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.677

Bravo AF: 0.713

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 06, 2022	- -

SHOX-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.46
Dann	Benign	0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28474801; hg19: chrX-619543; COSMIC: COSV61861140;