rs778921118

chrX-640862-G-CchrX-640862-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_000451.4(SHOX):c.528G>C(p.Glu176Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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 Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0660

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000451.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-640862-G-C is Pathogenic according to our data. Variant chrX-640862-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 265858.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39175665).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.528G>C	p.Glu176Asp	missense_variant	3/5	ENST00000686671.1
SHOX	NM_006883.2	c.528G>C	p.Glu176Asp	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.528G>C	p.Glu176Asp	missense_variant	3/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.528G>C	p.Glu176Asp	missense_variant	3/5	1
SHOX	ENST00000381578.6	c.528G>C	p.Glu176Asp	missense_variant	4/6	5		P1
SHOX	ENST00000334060.8	c.528G>C	p.Glu176Asp	missense_variant	4/6	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

SHOX-related short stature Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Human Genetics Disease in Children – Taif University, Taif University

Mar 03, 2016

Clinical investigation included measurement of weight (kg), standing height (cm), arm span (cm), sitting height (cm), calculation of subischeal leg length (cm) [height-sitting height], growth hormone deficiency test, and measurement of father’s height (cm) and mother’s height (cm). There is no family history. THis mutation is in the homeodomain DNA binding site of SHOX gene in exon 4 (c. 528G>C), which plays an important role in DNA binding, protein transactivation, cell cycle and growth regulation. Clement et al. (2000) stated that the homeodomain proteins have important physiological functions in regulating embryonic development in vertebrates, suggesting that the mutations in SHOX gene especially in homeodomain region may lead to developmental abnormalities. According to the PolyPhen-2 prediction program this mutation is predicted to be probably damaging and considered to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.81	T;T;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.21
MutPred		0.27		Loss of methylation at K174 (P = 0.1048);Loss of methylation at K174 (P = 0.1048);Loss of methylation at K174 (P = 0.1048);
MVP		0.80
MPC		1.5
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.61

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: rs778921118; hg19: chrX-601597;