rs746391025

chrX-644627-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000451.4(SHOX):c.870G>A(p.Leu290=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,496,816 control chromosomes in the GnomAD database, including 46 homozygotes. There are 1,678 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (28 hom., 741 hem., cov: 33)
  • Exomes 𝑓: 0.0016 (18 hom. 937 hem.)
• Consequence: SHOX NM_000451.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.33

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=-0.53).
• BP6: Variant X-644627-G-A is Benign according to our data. Variant chrX-644627-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00992 (1510/152234) while in subpopulation AFR AF= 0.0307 (1277/41564). AF 95% confidence interval is 0.0293. There are 28 homozygotes in gnomad4. There are 741 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.870G>A	p.Leu290=	synonymous_variant	5/5	ENST00000686671.1
SHOX	NM_006883.2	c.633+3540G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.870G>A	p.Leu290=	synonymous_variant	5/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.633+3540G>A		intron_variant		1
SHOX	ENST00000381578.6	c.870G>A	p.Leu290=	synonymous_variant	6/6	5		P1
SHOX	ENST00000334060.8	c.633+3540G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1502 AN: 152128 Hom.: 28 Cov.: 33 AF XY: 0.00984 AC XY: 731 AN XY: 74312

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00275 AC: 265 AN: 96440 Hom.: 1 AF XY: 0.00235 AC XY: 127 AN XY: 53952

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000540

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000977

Gnomad OTH exome AF: 0.00585

GnomAD4 exome AF: 0.00156 AC: 2093 AN: 1344582 Hom.: 18 Cov.: 32 AF XY: 0.00141 AC XY: 937 AN XY: 662750

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.00484

Gnomad4 ASJ exome AF: 0.00697

Gnomad4 EAS exome AF: 0.0000322

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.0000300

Gnomad4 NFE exome AF: 0.000474

Gnomad4 OTH exome AF: 0.00452

GnomAD4 genome AF: 0.00992 AC: 1510 AN: 152234 Hom.: 28 Cov.: 33 AF XY: 0.00996 AC XY: 741 AN XY: 74428

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000633

Gnomad4 OTH AF: 0.0118

Bravo AF: 0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 16, 2023

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	5.1
Dann	Benign	0.96

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: rs746391025; hg19: chrX-605362;