rs749355015

chrX-644677-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000451.4(SHOX):c.*41C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,396,558 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,019 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 0.0048 (7 hom., 371 hem., cov: 33)
  • Exomes 𝑓: 0.0011 (8 hom. 648 hem.)
• Consequence: SHOX NM_000451.4 3_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.329

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00111 (1376/1244334) while in subpopulation AFR AF= 0.0181 (440/24284). AF 95% confidence interval is 0.0167. There are 8 homozygotes in gnomad4_exome. There are 648 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.*41C>A		3_prime_UTR_variant	5/5	ENST00000686671.1
SHOX	NM_006883.2	c.633+3590C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.*41C>A		3_prime_UTR_variant	5/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.633+3590C>A		intron_variant		1
SHOX	ENST00000381578.6	c.*41C>A		3_prime_UTR_variant	6/6	5		P1
SHOX	ENST00000334060.8	c.633+3590C>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 725 AN: 152112 Hom.: 7 Cov.: 33 AF XY: 0.00494 AC XY: 367 AN XY: 74300

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00182 AC: 24 AN: 13208 Hom.: 1 AF XY: 0.00230 AC XY: 17 AN XY: 7394

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.00372

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000657

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00111 AC: 1376 AN: 1244334 Hom.: 8 Cov.: 31 AF XY: 0.00107 AC XY: 648 AN XY: 607386

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.00263

Gnomad4 ASJ exome AF: 0.000686

Gnomad4 EAS exome AF: 0.0000352

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000719

Gnomad4 OTH exome AF: 0.00251

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152224 Hom.: 7 Cov.: 33 AF XY: 0.00499 AC XY: 371 AN XY: 74422

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00284

Bravo AF: 0.00553

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SHOX-related short stature Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Human Genetics Disease in Children – Taif University, Taif University

Mar 03, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	2.1
Dann	Benign	0.42

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: rs749355015; hg19: chrX-605412;