rs146304983

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000451.4(SHOX):c.86A>C(p.Lys29Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000833 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 648 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., 26 hem., cov: 33)

Exomes 𝑓: 0.00088 ( 0 hom. 622 hem. )

Consequence

SHOX
NM_000451.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 4.96

Variant links:

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]

SHOX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14937094).

BP6

Variant X-630983-A-C is Benign according to our data. Variant chrX-630983-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93095.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00042 (64/152256) while in subpopulation NFE AF= 0.000765 (52/68010). AF 95% confidence interval is 0.000599. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4 link	c.86A>C	p.Lys29Thr	missense_variant	Exon 1 of 5	ENST00000686671.1	NP_000442.1	O15266-1A0A024R385
SHOX	NM_006883.2 link	c.86A>C	p.Lys29Thr	missense_variant	Exon 2 of 6		NP_006874.1	O15266-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHOX	ENST00000686671.1 link	c.86A>C	p.Lys29Thr	missense_variant	Exon 1 of 5		NM_000451.4	ENSP00000508521.1	O15266-1
SHOX	ENST00000381575.6 link	c.86A>C	p.Lys29Thr	missense_variant	Exon 1 of 5	1		ENSP00000370987.1	O15266-2
SHOX	ENST00000381578.6 link	c.86A>C	p.Lys29Thr	missense_variant	Exon 2 of 6	5		ENSP00000370990.1	O15266-1
SHOX	ENST00000334060.8 link	c.86A>C	p.Lys29Thr	missense_variant	Exon 2 of 6	5		ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74326

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000765

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000454

AC:

114

AN:

250928

Hom.:

AF XY:

0.000494

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000865

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000876

AC:

1280

AN:

1461468

Hom.:

Cov.:

AF XY:

0.000856

AC XY:

622

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000420

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000765

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000495

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Mar 06, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in hemizygous state in a patient with personal and family history of dyschondrosteosis, however the affected parent was the father and testing methods were not specified (Salmon-Musial et al., 2011); Observed in 2 unrelated patients referred for SHOX gene testing, however family studies showed the variant did not segregate with disease in one family (Bunyan et al., 2013).; This variant is associated with the following publications: (PMID: 21262861, 21912078, 23636926) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Dec 29, 2023

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SHOX c.86A>C (p.Lys29Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 250928 control chromosomes, predominantly at a frequency of 0.00087 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SHOX causing Leri-Weill Dyschondrosteosis phenotype (0.00025). c.86A>C has been reported in the literature in at least an individual with clinical features of Leri-Weill dyschondrosteosis (example: SalmonMusial_2011). Family studies showed that the variant did not segregate with disease in one family (example: Bunyan_2013). At least one publication reports experimental evidence evaluating an impact on protein function on SHOX-SOX6 interaction (AzaCarmona_2014). The most pronounced variant effect results in about 80% of the WT clones on a Yeast two-hybrid system, which suggest this variant apparently did not affect SHOX-SOX6 interaction. The following publications have been ascertained in the context of this evaluation (PMID: 24421874, 21912078, 23636926). ClinVar contains an entry for this variant (Variation ID: 93095). Based on the evidence outlined above, the variant was classified as likely benign. -

SHOX-related short stature

Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

T;.;.

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.53

T;T;.

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-1.4

N;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.062

T;D;D

Sift4G

Benign

0.068

T;T;T

Polyphen

0.95

P;P;P

Vest4

0.31

MVP

0.98

MPC

0.71

ClinPred

0.053

GERP RS

1.9

Varity_R

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over