rs139059497

Variant names:

• chrX-631017-G-A
• rs139059497
• NM_000451.4:c.120G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000451.4(SHOX):​c.120G>A​(p.Glu40Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000143 in 1,613,852 control chromosomes in the GnomAD database, including 1 homozygotes. There are 105 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., 42 hem., cov: 34)
  • Exomes 𝑓: 0.000090 (1 hom. 63 hem.)
• Consequence: SHOX NM_000451.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.84
• Publications: 0 publications found

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):

• Langer mesomelic dysplasia

  Inheritance: AR, XL, Unknown Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• Leri-Weill dyschondrosteosis

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
• SHOX-related short stature

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-631017-G-A is Benign according to our data. Variant chrX-631017-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00065 (99/152282) while in subpopulation AFR AF = 0.00224 (93/41554). AF 95% confidence interval is 0.00187. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 42 AR,XL,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000451.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	NM_000451.4	MANE Select	c.120G>A	p.Glu40Glu	synonymous	Exon 1 of 5	NP_000442.1	O15266-1
	SHOX	NM_006883.2		c.120G>A	p.Glu40Glu	synonymous	Exon 2 of 6	NP_006874.1	O15266-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000686671.1	MANE Select	c.120G>A	p.Glu40Glu	synonymous	Exon 1 of 5	ENSP00000508521.1	O15266-1
	SHOX	ENST00000381575.6	TSL:1	c.120G>A	p.Glu40Glu	synonymous	Exon 1 of 5	ENSP00000370987.1	O15266-2
	SHOX	ENST00000381578.6	TSL:5	c.120G>A	p.Glu40Glu	synonymous	Exon 2 of 6	ENSP00000370990.1	O15266-1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152164 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000227 AC: 57 AN: 250832 AF XY: 0.000236

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000903 AC: 132 AN: 1461570 Hom.: 1 Cov.: 30 AF XY: 0.0000866 AC XY: 63 AN XY: 727082

African (AFR) AF: 0.00227 AC: 76 AN: 33472

American (AMR) AF: 0.000313 AC: 14 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111838

Other (OTH) AF: 0.000182 AC: 11 AN: 60374

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152282 Hom.: 0 Cov.: 34 AF XY: 0.000564 AC XY: 42 AN XY: 74466

African (AFR) AF: 0.00224 AC: 93 AN: 41554

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Bravo AF: 0.000771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.6
DANN	Uncertain	0.98
PhyloP100		4.8
PromoterAI		-0.011	Neutral

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

Other links and lift over

dbSNP: rs139059497; hg19: chrX-591752;