rs193072890

Positions:

• chrX-658804-G-A
• chrX-658804-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006883.2(SHOX):​c.653G>A​(p.Arg218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 375,812 control chromosomes in the GnomAD database, including 27 homozygotes. There are 927 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., 807 hem., cov: 28)
  • Exomes 𝑓: 0.0010 (6 hom. 120 hem.)
• Consequence: SHOX NM_006883.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.627

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003453523).
• BP6: Variant X-658804-G-A is Benign according to our data. Variant chrX-658804-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448376.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1608/134346) while in subpopulation AFR AF= 0.042 (1473/35088). AF 95% confidence interval is 0.0402. There are 21 homozygotes in gnomad4. There are 807 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOX	NM_006883.2	c.653G>A	p.Arg218His	missense_variant	6/6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000381575.6	c.653G>A	p.Arg218His	missense_variant	5/5	1		ENSP00000370987.1
SHOX	ENST00000334060.8	c.653G>A	p.Arg218His	missense_variant	6/6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1607 AN: 134240 Hom.: 22 Cov.: 28 AF XY: 0.0125 AC XY: 804 AN XY: 64396

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000474

Gnomad FIN AF: 0.000257

Gnomad MID AF: 0.0156

Gnomad NFE AF: 0.000593

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00129 AC: 125 AN: 97022 Hom.: 2 AF XY: 0.00107 AC XY: 57 AN XY: 53472

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00104 AC: 252 AN: 241466 Hom.: 6 Cov.: 0 AF XY: 0.000856 AC XY: 120 AN XY: 140114

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000330

Gnomad4 FIN exome AF: 0.000186

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.0120 AC: 1608 AN: 134346 Hom.: 21 Cov.: 28 AF XY: 0.0125 AC XY: 807 AN XY: 64514

Gnomad4 AFR AF: 0.0420

Gnomad4 AMR AF: 0.00548

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000476

Gnomad4 FIN AF: 0.000257

Gnomad4 NFE AF: 0.000609

Gnomad4 OTH AF: 0.0114

Bravo AF: 0.0134

ExAC AF: 0.000781 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SHOX: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 17, 2021	- -

SHOX-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.72
DANN	Benign	0.82
FATHMM_MKL	Benign	0.00047	N
LIST_S2	Benign	0.30	T;.
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.38	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.14
Sift	Benign	0.13	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0	B;B
Vest4		0.070
MVP		0.53
ClinPred		0.0032	T

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193072890; hg19: chrX-619539;