rs752189039

Positions:

• chrX-641001-G-A
• chrX-641001-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000451.4(SHOX):​c.547G>A​(p.Val183Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,613,816 control chromosomes in the GnomAD database, including 1 homozygotes. There are 239 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 12 hem., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom. 227 hem.)
• Consequence: SHOX NM_000451.4 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.70

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013013542).
• BP6: Variant X-641001-G-A is Benign according to our data. Variant chrX-641001-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOX	NM_000451.4	c.547G>A	p.Val183Ile	missense_variant, splice_region_variant	4/5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.547G>A	p.Val183Ile	missense_variant, splice_region_variant	5/6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.547G>A	p.Val183Ile	missense_variant, splice_region_variant	4/5		NM_000451.4	ENSP00000508521	P1
SHOX	ENST00000381575.6	c.547G>A	p.Val183Ile	missense_variant, splice_region_variant	4/5	1		ENSP00000370987
SHOX	ENST00000381578.6	c.547G>A	p.Val183Ile	missense_variant, splice_region_variant	5/6	5		ENSP00000370990	P1
SHOX	ENST00000334060.8	c.547G>A	p.Val183Ile	missense_variant, splice_region_variant	5/6	5		ENSP00000335505

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74300

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000470 AC: 118 AN: 251158 Hom.: 1 AF XY: 0.000597 AC XY: 81 AN XY: 135742

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1461564 Hom.: 1 Cov.: 33 AF XY: 0.000312 AC XY: 227 AN XY: 727092

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00311

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74428

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000117

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2022	- -

SHOX-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2022

This variant is classified as likely 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	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.49	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.091	T;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.75	P;P;P
Vest4		0.14
MutPred		0.35		Loss of MoRF binding (P = 0.1078);Loss of MoRF binding (P = 0.1078);Loss of MoRF binding (P = 0.1078);
MVP		0.71
MPC		0.88
ClinPred		0.088	T
GERP RS		1.5
Varity_R		0.090

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: rs752189039; hg19: chrX-601736; COSMIC: COSV105219284;