rs1556457962

Positions:

• chrX-631133-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000451.4(SHOX):​c.236A>T​(p.Lys79Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom. 1 hem.)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33425158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOX	NM_000451.4	c.236A>T	p.Lys79Met	missense_variant	1/5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.236A>T	p.Lys79Met	missense_variant	2/6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.236A>T	p.Lys79Met	missense_variant	1/5		NM_000451.4	ENSP00000508521	P1
SHOX	ENST00000381575.6	c.236A>T	p.Lys79Met	missense_variant	1/5	1		ENSP00000370987
SHOX	ENST00000381578.6	c.236A>T	p.Lys79Met	missense_variant	2/6	5		ENSP00000370990	P1
SHOX	ENST00000334060.8	c.236A>T	p.Lys79Met	missense_variant	2/6	5		ENSP00000335505

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461212 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726892

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SHOX-related short stature Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MVZ Dr. Eberhard & Partner Dortmund

Jan 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D;.
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	0.050	D
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.95	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.054	T;D;D
Sift4G	Benign	0.087	T;T;T
Polyphen		0.84	P;P;P
Vest4		0.24
MutPred		0.50		Loss of ubiquitination at K79 (P = 0.0118);Loss of ubiquitination at K79 (P = 0.0118);Loss of ubiquitination at K79 (P = 0.0118);
MVP		0.90
MPC		1.3
ClinPred		0.72	D
GERP RS		2.3
Varity_R		0.21

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: rs1556457962; hg19: chrX-591868;