rs778186580

Variant names:

• chrX-630887-CG-C
• rs778186580
• NM_000451.4:c.-9delG

Your query was ambiguous. Multiple possible variants found:

• chrX-630887-CG-C
• chrX-630887-CG-CGG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000451.4(SHOX):​c.-9delG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000624 in 1,612,664 control chromosomes in the GnomAD database, including 2 homozygotes. There are 517 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., 23 hem., cov: 33)
  • Exomes 𝑓: 0.00065 (2 hom. 494 hem.)
• Consequence: SHOX NM_000451.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.25
• Publications: 1 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: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Langer mesomelic dysplasia

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant X-630887-CG-C is Benign according to our data. Variant chrX-630887-CG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586583.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000394 (60/152172) while in subpopulation NFE AF = 0.000794 (54/68032). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 23 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.-9delG		5_prime_UTR	Exon 1 of 5	NP_000442.1	O15266-1
	SHOX	NM_006883.2		c.-9delG		5_prime_UTR	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.-9delG		5_prime_UTR	Exon 1 of 5	ENSP00000508521.1	O15266-1
	SHOX	ENST00000381575.6	TSL:1	c.-9delG		5_prime_UTR	Exon 1 of 5	ENSP00000370987.1	O15266-2
	SHOX	ENST00000381578.6	TSL:5	c.-9delG		5_prime_UTR	Exon 2 of 6	ENSP00000370990.1	O15266-1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000437 AC: 109 AN: 249470 AF XY: 0.000443

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: 0.0000462

Gnomad NFE exome AF: 0.000953

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000648 AC: 946 AN: 1460492 Hom.: 2 Cov.: 30 AF XY: 0.000680 AC XY: 494 AN XY: 726518

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44714

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.0000380 AC: 2 AN: 52598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.000828 AC: 921 AN: 1111782

Other (OTH) AF: 0.000348 AC: 21 AN: 60328

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74326

African (AFR) AF: 0.0000965 AC: 4 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Bravo AF: 0.000397

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=293/7	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs778186580;

hg19: chrX-591622;