rs2283679

Variant names:

• chrX-631617-T-C
• rs2283679
• NM_000451.4:c.277+443T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000451.4(SHOX):​c.277+443T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 151,950 control chromosomes in the GnomAD database, including 40,308 homozygotes. There are 54,112 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.

• Frequency: Genomes: 𝑓 0.73 (40308 hom., 54112 hem., cov: 33)
• Consequence: SHOX NM_000451.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.486
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4	c.277+443T>C		intron_variant	Intron 1 of 4	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.277+443T>C		intron_variant	Intron 2 of 5		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.277+443T>C		intron_variant	Intron 1 of 4		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.277+443T>C		intron_variant	Intron 1 of 4	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.277+443T>C		intron_variant	Intron 2 of 5	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.277+443T>C		intron_variant	Intron 2 of 5	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110352 AN: 151830 Hom.: 40271 Cov.: 33

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.812

Gnomad MID AF: 0.729

Gnomad NFE AF: 0.755

Gnomad OTH AF: 0.713

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.727 AC: 110441 AN: 151950 Hom.: 40308 Cov.: 33 AF XY: 0.729 AC XY: 54112 AN XY: 74258

African (AFR) AF: 0.671 AC: 27833 AN: 41452

American (AMR) AF: 0.723 AC: 11044 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2438 AN: 3466

East Asian (EAS) AF: 0.683 AC: 3534 AN: 5172

South Asian (SAS) AF: 0.713 AC: 3429 AN: 4812

European-Finnish (FIN) AF: 0.812 AC: 8571 AN: 10558

Middle Eastern (MID) AF: 0.723 AC: 211 AN: 292

European-Non Finnish (NFE) AF: 0.755 AC: 51261 AN: 67910

Other (OTH) AF: 0.713 AC: 1499 AN: 2102

Bravo AF: 0.714

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.12
PhyloP100		-0.49

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: rs2283679; hg19: chrX-592352; COSMIC: COSV61861242;