X-624528-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006883.2(SHOX):c.-507G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 151,914 control chromosomes in the GnomAD database, including 6,117 homozygotes. There are 20,647 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6115 hom., 20636 hem., cov: 30)
  • Exomes 𝑓: 0.28 (2 hom. 11 hem.)
• Consequence: SHOX NM_006883.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter P:1 B:4
• Conservation: PhyloP100: -0.581

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-624528-G-C is Benign according to our data. Variant chrX-624528-G-C is described in ClinVar as [Benign]. Clinvar id is 191361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_006883.2	c.-507G>C		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000334060.8	c.-507G>C		5_prime_UTR_variant	1/6	5
SHOX	ENST00000381578.6	c.-507G>C		5_prime_UTR_variant	1/6	5		P1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42360 AN: 151736 Hom.: 6111 Cov.: 30 AF XY: 0.278 AC XY: 20615 AN XY: 74072

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.287

GnomAD4 exome AF: 0.283 AC: 17 AN: 60 Hom.: 2 Cov.: 0 AF XY: 0.262 AC XY: 11 AN XY: 42

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.279 AC: 42375 AN: 151854 Hom.: 6115 Cov.: 30 AF XY: 0.278 AC XY: 20636 AN XY: 74200

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.327

Gnomad4 OTH AF: 0.291

Bravo AF: 0.275

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

SHOX-related short stature Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	not provided	Genetics Research Lab, Taif University	-	- -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000451.3:c.-507G>C in the gene SHOX has an allele frequency of 0.327 in East Asian subpopulation in the gnomAD database, including 1343 homozygous occurrences. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.13
Dann	Benign	0.54

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: rs111549748; hg19: chrX-585263;