ENST00000381578:c.-512C>A

Variant names:

• chrX-624523-C-A
• rs113313554
• ENST00000381578:c.-512C>A

Variant summary

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

The ENST00000381578(SHOX):​c.-512C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 152,102 control chromosomes in the GnomAD database, including 74 homozygotes. There are 2,048 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 0.029 (74 hom., 2045 hem., cov: 30)
  • Exomes 𝑓: 0.038 (0 hom. 3 hem.)
• Consequence: SHOX ENST00000381578 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 B:4
• Conservation: PhyloP100: 0.0200

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=-0.78).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0288 (4383/152024) while in subpopulation AFR AF= 0.0413 (1711/41470). AF 95% confidence interval is 0.0396. There are 74 homozygotes in gnomad4. There are 2045 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 74 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_006883.2	c.-512C>A		5_prime_UTR_variant	Exon 1 of 6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000381578	c.-512C>A		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060	c.-512C>A		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4384 AN: 151906 Hom.: 73 Cov.: 30 AF XY: 0.0275 AC XY: 2041 AN XY: 74170

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00789

Gnomad FIN AF: 0.00634

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0450

GnomAD4 exome AF: 0.0385 AC: 3 AN: 78 Hom.: 0 Cov.: 0 AF XY: 0.0536 AC XY: 3 AN XY: 56

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.0288 AC: 4383 AN: 152024 Hom.: 74 Cov.: 30 AF XY: 0.0275 AC XY: 2045 AN XY: 74298

Gnomad4 AFR AF: 0.0413

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00769

Gnomad4 FIN AF: 0.00634

Gnomad4 NFE AF: 0.0261

Gnomad4 OTH AF: 0.0445

Bravo AF: 0.0321

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:4

Revision: no assertion criteria provided

Submissions by phenotype

SHOX-related short stature Pathogenic:1 Benign:1

-

Genetics Research Lab, Taif University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: not provided

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

NM_000451.3:c.-512C>A in SHOX gene has an allele frequency of 0.042 in African subpopulation in the gnomAD database, including 15 homozygous occurrences. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2. -

not specified Benign:1

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

SHOX-related disorder Benign:1

May 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.8
DANN	Benign	0.58

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: rs113313554; hg19: chrX-585258;