rs397514461

Positions:

• chrX-640842-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5

The NM_000451.4(SHOX):​c.508G>C​(p.Ala170Pro) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A170D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.80

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 13 ACMG points.

• PS1: Transcript NM_000451.4 (SHOX) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 29994
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000451.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-640843-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 29995.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant X-640842-G-C is Pathogenic according to our data. Variant chrX-640842-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 29994.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-640842-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.508G>C	p.Ala170Pro	missense_variant	3/5	ENST00000686671.1
SHOX	NM_006883.2	c.508G>C	p.Ala170Pro	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.508G>C	p.Ala170Pro	missense_variant	3/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.508G>C	p.Ala170Pro	missense_variant	3/5	1
SHOX	ENST00000381578.6	c.508G>C	p.Ala170Pro	missense_variant	4/6	5		P1
SHOX	ENST00000334060.8	c.508G>C	p.Ala170Pro	missense_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Leri-Weill dyschondrosteosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2011

- -

Langer mesomelic dysplasia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.5	H;H;H
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.83	P;P;P
Vest4		0.86
MutPred		0.76		Gain of glycosylation at A170 (P = 0.0028);Gain of glycosylation at A170 (P = 0.0028);Gain of glycosylation at A170 (P = 0.0028);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		1.4
Varity_R		0.99

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: rs397514461; hg19: chrX-601577;