rs146304983

chrX-630983-A-CchrX-630983-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.96

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a chain Short stature homeobox protein (size 291) in uniprot entity SHOX_HUMAN there are 19 pathogenic changes around while only 3 benign (86%) in NM_000451.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.14937094).
• BS2: High Hemizygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.86A>C	p.Lys29Thr	missense_variant	1/5	ENST00000686671.1
SHOX	NM_006883.2	c.86A>C	p.Lys29Thr	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.86A>C	p.Lys29Thr	missense_variant	1/5		NM_000451.4	P1
SHOX	ENST00000381575.6	c.86A>C	p.Lys29Thr	missense_variant	1/5	1
SHOX	ENST00000381578.6	c.86A>C	p.Lys29Thr	missense_variant	2/6	5		P1
SHOX	ENST00000334060.8	c.86A>C	p.Lys29Thr	missense_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26 AN XY: 74326

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.: 0 AF XY: 0.000494 AC XY: 67 AN XY: 135690

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.: 0 Cov.: 30 AF XY: 0.000856 AC XY: 622 AN XY: 727052

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: 64 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74454

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: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2021	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2013	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2023	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. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in SHOX causing Leri-Weill Dyschondrosteosis phenotype (0.00025), strongly suggesting that the variant is benign. c.86A>C has been reported in the literature in individuals with features of Leri-Weill Dyschondrosteosis including mesomelia, clinical or radiological Madelung deformity and family history, without strong evidence for causality (example, SalmonMusial_2011). Family studies showed 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). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

SHOX-related short stature Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;.
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.53	T;T;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.96	D
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	T
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

Other links and lift over

dbSNP: rs146304983; hg19: chrX-591718;