rs137852553

chrX-641051-C-GchrX-641051-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000451.4(SHOX):c.597C>G(p.Tyr199Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOX NM_000451.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.528

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-641051-C-G is Pathogenic according to our data. Variant chrX-641051-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9873.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-641051-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.597C>G	p.Tyr199Ter	stop_gained	4/5	ENST00000686671.1
SHOX	NM_006883.2	c.597C>G	p.Tyr199Ter	stop_gained	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.597C>G	p.Tyr199Ter	stop_gained	4/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.597C>G	p.Tyr199Ter	stop_gained	4/5	1
SHOX	ENST00000381578.6	c.597C>G	p.Tyr199Ter	stop_gained	5/6	5		P1
SHOX	ENST00000334060.8	c.597C>G	p.Tyr199Ter	stop_gained	5/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leri-Weill dyschondrosteosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	30
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.30	N
MutationTaster	Benign	1.0	D;D;D;D;D;D
Vest4		0.97
GERP RS		-0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852553; hg19: chrX-601786;