chrX-630960-C-T

Position:

• chrX-630960-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000451.4(SHOX):​c.63C>T​(p.Gly21=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00577 in 1,613,250 control chromosomes in the GnomAD database, including 39 homozygotes. There are 4,541 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G21G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., 289 hem., cov: 33)
  • Exomes 𝑓: 0.0059 (34 hom. 4252 hem.)
• Consequence: SHOX NM_000451.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.389

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-630960-C-T is Benign according to our data. Variant chrX-630960-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-630960-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.389 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.63C>T	p.Gly21=	synonymous_variant	1/5	ENST00000686671.1
SHOX	NM_006883.2	c.63C>T	p.Gly21=	synonymous_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.63C>T	p.Gly21=	synonymous_variant	1/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.63C>T	p.Gly21=	synonymous_variant	1/5	1
SHOX	ENST00000381578.6	c.63C>T	p.Gly21=	synonymous_variant	2/6	5		P1
SHOX	ENST00000334060.8	c.63C>T	p.Gly21=	synonymous_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 631 AN: 152140 Hom.: 5 Cov.: 33 AF XY: 0.00389 AC XY: 289 AN XY: 74324

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00665

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00425 AC: 1066 AN: 250868 Hom.: 8 AF XY: 0.00426 AC XY: 578 AN XY: 135678

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.00617

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00594 AC: 8681 AN: 1460992 Hom.: 34 Cov.: 30 AF XY: 0.00585 AC XY: 4252 AN XY: 726800

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00597

Gnomad4 NFE exome AF: 0.00679

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00414 AC: 631 AN: 152258 Hom.: 5 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74452

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00593

Gnomad4 NFE AF: 0.00665

Gnomad4 OTH AF: 0.00236

Bravo AF: 0.00347

EpiCase AF: 0.00687

EpiControl AF: 0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Leri-Weill dyschondrosteosis;C0432230:Langer mesomelic dysplasia syndrome;C1845118:SHOX-related short stature Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 16, 2022

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 15, 2021

- -

SHOX-related short stature Other:1

not provided, no classification provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 11, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.4
DANN	Benign	0.81

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: rs142306835; hg19: chrX-591695;