X-630833-C-A

Variant summary

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

The NM_000451.4(SHOX):c.-65C>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 0.0000269 in 1,598,724 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., 5 hem., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom. 17 hem.)
• Consequence: SHOX NM_000451.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.08

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=-0.74).
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.-65C>A		5_prime_UTR_variant	1/5	ENST00000686671.1
SHOX	NM_006883.2	c.-65C>A		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.-65C>A		5_prime_UTR_variant	1/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.-65C>A		5_prime_UTR_variant	1/5	1
SHOX	ENST00000334060.8	c.-65C>A		5_prime_UTR_variant	2/6	5
SHOX	ENST00000381578.6	c.-65C>A		5_prime_UTR_variant	2/6	5		P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151960 Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 5 AN XY: 74224

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.0000249 AC: 36 AN: 1446764 Hom.: 0 Cov.: 28 AF XY: 0.0000236 AC XY: 17 AN XY: 719592

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151960 Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 5 AN XY: 74224

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.000957

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2023	Variant summary: HOX c.-65C>A is located in the untranslated mRNA region upstream of the initiation codon. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.7e-05 in 1598724 control chromosomes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in SHOX causing Leri-Weill Dyschondrosteosis (2.7e-05 vs 0.00025), allowing no conclusion about variant significance. c.-65C>A has been reported in the literature in individuals affected with Leri-Weill Dyschondrosteosis or suspected skeletal dysplasia (Grigelioniene_2001, Scocchia_2021). These reports do not provide unequivocal conclusions about association of the variant with Leri-Weill Dyschondrosteosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11735031, 34627339). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

SHOX-related short stature Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Oct 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	11
Dann	Benign	0.51

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: rs922062046; hg19: chrX-591568;