rs137852555

Positions:

• chrX-634798-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PP3_Moderate PP5

The NM_000451.4(SHOX):​c.458G>T​(p.Arg153Leu) variant causes a missense change involving the alteration of a 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). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.09

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 Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_000451.4 (SHOX) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 9876
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000451.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant X-634798-G-T is Pathogenic according to our data. Variant chrX-634798-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 9876.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-634798-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.458G>T	p.Arg153Leu	missense_variant	2/5	ENST00000686671.1
SHOX	NM_006883.2	c.458G>T	p.Arg153Leu	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.458G>T	p.Arg153Leu	missense_variant	2/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.458G>T	p.Arg153Leu	missense_variant	2/5	1
SHOX	ENST00000381578.6	c.458G>T	p.Arg153Leu	missense_variant	3/6	5		P1
SHOX	ENST00000334060.8	c.458G>T	p.Arg153Leu	missense_variant	3/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Mar 15, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.80
MutPred		0.73		Loss of MoRF binding (P = 0.0252);Loss of MoRF binding (P = 0.0252);Loss of MoRF binding (P = 0.0252);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		2.0
Varity_R		0.94

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: rs137852555; hg19: chrX-595533;