rs146304983

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2BP4_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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Leri-Weill dyschondrosteosis
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Langer mesomelic dysplasia
Inheritance: Unknown, XL, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
SHOX-related short stature
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SHOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.53811 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, SHOX-related short stature.

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 VariationId is 93095.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 26 XL,Unknown,AR,AD 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.:

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

GnomAD2 exomes

AF:

0.000454

AC:

114

AN:

250928

AF XY:

0.000494

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.000269

AC:

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00110

AC:

1218

AN:

1111826

Other (OTH)

AF:

0.000762

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

170

256

341

426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000420

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41556

American (AMR)

AF:

0.000327

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000765

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

- -

Jun 28, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inherited from the affected father in a male patient with personal and family history of dyschondrosteosis (PMID: 21912078); Observed in 2 unrelated patients referred for SHOX gene testing, however family studies showed the variant did not segregate with disease in one family (PMID: 23636926); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21262861, 34426522, Sobieszczaska-Drodziel[CaseReport], 23636926, 21912078) -

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

(source)

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

PhyloP100

5.0

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

PromoterAI

-0.17

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over