rs369390009

Variant names:

• chrX-644919-A-AAG
• rs369390009
• NM_000451.4:c.*284_*285dupAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000451.4(SHOX):​c.*284_*285dupAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 432,518 control chromosomes in the GnomAD database, including 6,669 homozygotes. There are 36,827 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.16 (2073 hom., 11624 hem., cov: 29)
  • Exomes 𝑓: 0.18 (4596 hom. 25203 hem.)
• Consequence: SHOX NM_000451.4 3_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.336
• 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4	c.*284_*285dupAG		3_prime_UTR_variant	Exon 5 of 5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.633+3833_633+3834dupAG		intron_variant	Intron 5 of 5		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.*284_*285dupAG		3_prime_UTR_variant	Exon 5 of 5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.633+3833_633+3834dupAG		intron_variant	Intron 4 of 4	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.*284_*285dupAG		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.633+3833_633+3834dupAG		intron_variant	Intron 5 of 5	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24110 AN: 151980 Hom.: 2072 Cov.: 29

Gnomad AFR AF: 0.0955

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0950

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.176 AC: 49285 AN: 280420 Hom.: 4596 Cov.: 3 AF XY: 0.176 AC XY: 25203 AN XY: 143316

African (AFR) AF: 0.0962 AC: 624 AN: 6488

American (AMR) AF: 0.202 AC: 1323 AN: 6562

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 2420 AN: 9222

East Asian (EAS) AF: 0.0930 AC: 1853 AN: 19920

South Asian (SAS) AF: 0.129 AC: 1831 AN: 14218

European-Finnish (FIN) AF: 0.166 AC: 3982 AN: 23930

Middle Eastern (MID) AF: 0.241 AC: 331 AN: 1372

European-Non Finnish (NFE) AF: 0.186 AC: 33711 AN: 180808

Other (OTH) AF: 0.179 AC: 3210 AN: 17900

GnomAD4 genome AF: 0.159 AC: 24115 AN: 152098 Hom.: 2073 Cov.: 29 AF XY: 0.156 AC XY: 11624 AN XY: 74350

African (AFR) AF: 0.0953 AC: 3953 AN: 41500

American (AMR) AF: 0.213 AC: 3258 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3472

East Asian (EAS) AF: 0.0950 AC: 491 AN: 5168

South Asian (SAS) AF: 0.129 AC: 621 AN: 4826

European-Finnish (FIN) AF: 0.143 AC: 1513 AN: 10594

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12717 AN: 67934

Other (OTH) AF: 0.183 AC: 387 AN: 2116

Bravo AF: 0.167

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SHOX-related short stature Uncertain:1

Mar 03, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369390009; hg19: chrX-605654;