X-624523-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006883.2(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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (74 hom., 2045 hem., cov: 30)
  • Exomes 𝑓: 0.038 (0 hom. 3 hem.)
• Consequence: SHOX NM_006883.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-624523-C-A is Benign according to our data. Variant chrX-624523-C-A is described in ClinVar as [Benign]. Clinvar id is 191362.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• BS2: High Homozygotes in GnomAd at 73 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_006883.2	c.-512C>A		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000334060.8	c.-512C>A		5_prime_UTR_variant	1/6	5
SHOX	ENST00000381578.6	c.-512C>A		5_prime_UTR_variant	1/6	5		P1

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: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

SHOX-related short stature Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, no assertion criteria provided	not provided	Genetics Research Lab, Taif University	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

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- -

SHOX-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2022

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

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

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;