X-630843-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000451.4(SHOX):c.-55C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,607,792 control chromosomes in the GnomAD database, including 20 homozygotes. There are 3,012 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., 199 hem., cov: 33)
  • Exomes 𝑓: 0.0040 (17 hom. 2813 hem.)
• Consequence: SHOX NM_000451.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 1.54

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.-55C>T		5_prime_UTR_variant	1/5	ENST00000686671.1
SHOX	NM_006883.2	c.-55C>T		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.-55C>T		5_prime_UTR_variant	1/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.-55C>T		5_prime_UTR_variant	1/5	1
SHOX	ENST00000334060.8	c.-55C>T		5_prime_UTR_variant	2/6	5
SHOX	ENST00000381578.6	c.-55C>T		5_prime_UTR_variant	2/6	5		P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152166 Hom.: 3 Cov.: 33 AF XY: 0.00268 AC XY: 199 AN XY: 74332

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00401 AC: 5840 AN: 1455508 Hom.: 17 Cov.: 29 AF XY: 0.00389 AC XY: 2813 AN XY: 723758

Gnomad4 AFR exome AF: 0.000451

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.000576

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00128

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.00405

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152284 Hom.: 3 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74460

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00440

Gnomad4 OTH AF: 0.00520

Bravo AF: 0.00324

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

May 20, 2015

- -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 21, 2020

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 17, 2018

- -

SHOX-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2020

This variant is classified as likely 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	-0.69
Cadd	Benign	12
Dann	Benign	0.73

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: rs772910213; hg19: chrX-591578; COSMIC: COSV61861031;