rs137852559

Positions:

• chrX-644634-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000451.4(SHOX):​c.877T>C​(p.Ter293Argext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SHOX NM_000451.4 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.38

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000451.4 Downstream stopcodon found after 327 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOX	NM_000451.4	c.877T>C	p.Ter293Argext*?	stop_lost	5/5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.633+3547T>C		intron_variant			NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.877T>C	p.Ter293Argext*?	stop_lost	5/5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.633+3547T>C		intron_variant		1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.877T>C	p.Ter293Argext*?	stop_lost	6/6	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.633+3547T>C		intron_variant		5		ENSP00000335505.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1324448 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 652294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leri-Weill dyschondrosteosis Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 08, 2020	The SHOX c.877T>C variant is a single nucleotide change from a thymine to a cytosine in exon 6 of the SHOX gene resulting in the abolition of the termination codon and an extension of the wild type protein by an additional 48 amino acids (PM4). The variant has been reported in a patient with Leri-Weill dyschondrosteosis and his similarly affected mother (PMID: 15356038) (PS4_supporting). The variant has been reported in dbSNP (rs137852559) but is absent from population databases (PM2). The SHOX gene is constraint for loss of function variants. The variant has not been reported in disease databases to date. The variant is paternally inherited. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Benign	0.76
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.15
GERP RS		1.6

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: rs137852559; hg19: chrX-605369;