rs28474801

Variant names:

• chrX-658808-G-A
• rs28474801
• ENST00000381575.6:c.657G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-658808-G-A
• chrX-658808-G-C
• chrX-658808-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006883.2(SHOX):​c.657G>A​(p.Pro219Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 384,448 control chromosomes in the GnomAD database, including 83,240 homozygotes. There are 135,716 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37556 hom., 50134 hem., cov: 23)
  • Exomes 𝑓: 0.61 (45684 hom. 85582 hem.)
• Consequence: SHOX NM_006883.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.07
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-658808-G-A is Benign according to our data. Variant chrX-658808-G-A is described in ClinVar as Benign. ClinVar VariationId is 586580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006883.2. 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_006883.2		c.657G>A	p.Pro219Pro	synonymous	Exon 6 of 6	NP_006874.1	O15266-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000381575.6	TSL:1	c.657G>A	p.Pro219Pro	synonymous	Exon 5 of 5	ENSP00000370987.1	O15266-2
	SHOX	ENST00000334060.8	TSL:5	c.657G>A	p.Pro219Pro	synonymous	Exon 6 of 6	ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes AF: 0.704 AC: 103690 AN: 147328 Hom.: 37509 Cov.: 23

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.676

GnomAD2 exomes AF: 0.602 AC: 56209 AN: 93302 AF XY: 0.609

Gnomad AFR exome AF: 0.857

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.660

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.581

GnomAD4 exome AF: 0.612 AC: 145133 AN: 237004 Hom.: 45684 Cov.: 0 AF XY: 0.622 AC XY: 85582 AN XY: 137582

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.866 AC: 4546 AN: 5250

American (AMR) AF: 0.554 AC: 12204 AN: 22024

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 4813 AN: 8894

East Asian (EAS) AF: 0.683 AC: 3957 AN: 5796

South Asian (SAS) AF: 0.674 AC: 31980 AN: 47418

European-Finnish (FIN) AF: 0.540 AC: 5700 AN: 10556

Middle Eastern (MID) AF: 0.678 AC: 568 AN: 838

European-Non Finnish (NFE) AF: 0.595 AC: 74671 AN: 125432

Other (OTH) AF: 0.620 AC: 6694 AN: 10796

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.704 AC: 103795 AN: 147444 Hom.: 37556 Cov.: 23 AF XY: 0.701 AC XY: 50134 AN XY: 71512

African (AFR) AF: 0.892 AC: 35824 AN: 40168

American (AMR) AF: 0.630 AC: 9249 AN: 14692

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1978 AN: 3444

East Asian (EAS) AF: 0.734 AC: 3579 AN: 4874

South Asian (SAS) AF: 0.696 AC: 3222 AN: 4632

European-Finnish (FIN) AF: 0.570 AC: 5309 AN: 9314

Middle Eastern (MID) AF: 0.704 AC: 200 AN: 284

European-Non Finnish (NFE) AF: 0.633 AC: 42482 AN: 67106

Other (OTH) AF: 0.677 AC: 1378 AN: 2034

Bravo AF: 0.713

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	SHOX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.46
DANN	Benign	0.63
PhyloP100		-1.1

Splicing

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

Other links and lift over

dbSNP: rs28474801; hg19: chrX-619543; COSMIC: COSV61861140;