X-658808-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_006883.2(SHOX):​c.657G>T​(p.Pro219Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 244,548 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P219P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000033 (0 hom. 8 hem.)
• Consequence: SHOX NM_006883.2 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL,Unknown,AR,AD gene

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>T	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>T	p.Pro219Pro	synonymous	Exon 5 of 5	ENSP00000370987.1	O15266-2
	SHOX	ENST00000334060.8	TSL:5	c.657G>T	p.Pro219Pro	synonymous	Exon 6 of 6	ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000214 AC: 2 AN: 93302 AF XY: 0.0000388

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000327 AC: 8 AN: 244548 Hom.: 0 Cov.: 0 AF XY: 0.0000564 AC XY: 8 AN XY: 141880

African (AFR) AF: 0.00 AC: 0 AN: 5336

American (AMR) AF: 0.00 AC: 0 AN: 22836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9212

East Asian (EAS) AF: 0.00 AC: 0 AN: 5998

South Asian (SAS) AF: 0.000163 AC: 8 AN: 49030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 854

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 129226

Other (OTH) AF: 0.00 AC: 0 AN: 11120

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.52
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;