X-658804-G-T

Variant names:

• chrX-658804-G-T
• rs193072890
• ENST00000381575.6:c.653G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The ENST00000381575.6(SHOX):​c.653G>T​(p.Arg218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 28)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SHOX ENST00000381575.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.627
• 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: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.53811 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, SHOX-related short stature.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0807493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_006883.2	c.653G>T	p.Arg218Leu	missense_variant	Exon 6 of 6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000381575.6	c.653G>T	p.Arg218Leu	missense_variant	Exon 5 of 5	1		ENSP00000370987.1
SHOX	ENST00000334060.8	c.653G>T	p.Arg218Leu	missense_variant	Exon 6 of 6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 134260 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 97022 AF XY: 0.00

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 241518 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 140138

African (AFR) AF: 0.00 AC: 0 AN: 5146

American (AMR) AF: 0.00 AC: 0 AN: 22920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9188

East Asian (EAS) AF: 0.00 AC: 0 AN: 5806

South Asian (SAS) AF: 0.00 AC: 0 AN: 48478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 844

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 127408

Other (OTH) AF: 0.00 AC: 0 AN: 10956

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 134260 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 64406

African (AFR) AF: 0.00 AC: 0 AN: 34992

American (AMR) AF: 0.00 AC: 0 AN: 12572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3352

East Asian (EAS) AF: 0.00 AC: 0 AN: 4394

South Asian (SAS) AF: 0.00 AC: 0 AN: 4218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64058

Other (OTH) AF: 0.00 AC: 0 AN: 1832

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.36
DANN	Benign	0.71
FATHMM_MKL	Benign	0.00093	N
LIST_S2	Benign	0.26	T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.45	T
PhyloP100		-0.63
PROVEAN	Benign	2.0	N;N
REVEL	Benign	0.16
Sift	Benign	0.15	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0020	B;B
Vest4		0.24
MutPred		0.49		Loss of MoRF binding (P = 0.0537);Loss of MoRF binding (P = 0.0537);
MVP		0.41
ClinPred		0.089	T
Mutation Taster		=94/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs193072890; hg19: chrX-619539;