dbSNP rs137852559: SHOX:p.Ter293Argext*? (chrX-644634-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The NM_000451.4(SHOX):c.877T>C(p.Ter293Argext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SHOX
NM_000451.4 stop_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.38

Publications

0 publications found

Variant links:

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

SHOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Stoplost variant in NM_000451.4 Downstream stopcodon found after 327 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4 link	c.877T>C	p.Ter293Argext*?	stop_lost	Exon 5 of 5	ENST00000686671.1	NP_000442.1	O15266-1A0A024R385
SHOX	NM_006883.2 link	c.633+3547T>C		intron_variant	Intron 5 of 5		NP_006874.1	O15266-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHOX	ENST00000686671.1 link	c.877T>C	p.Ter293Argext*?	stop_lost	Exon 5 of 5		NM_000451.4	ENSP00000508521.1	O15266-1
SHOX	ENST00000381575.6 link	c.633+3547T>C		intron_variant	Intron 4 of 4	1		ENSP00000370987.1	O15266-2
SHOX	ENST00000381578.6 link	c.877T>C	p.Ter293Argext*?	stop_lost	Exon 6 of 6	5		ENSP00000370990.1	O15266-1
SHOX	ENST00000334060.8 link	c.633+3547T>C		intron_variant	Intron 5 of 5	5		ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1324448

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

652294

African (AFR)

AF:

0.00

AC:

AN:

26634

American (AMR)

AF:

0.00

AC:

AN:

26764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23102

East Asian (EAS)

AF:

0.00

AC:

AN:

29654

South Asian (SAS)

AF:

0.00

AC:

AN:

72818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3880

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1053586

Other (OTH)

AF:

0.00

AC:

AN:

54952

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leri-Weill dyschondrosteosis

Pathogenic:1Uncertain:1

Sep 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 08, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SHOX c.877T>C variant is a single nucleotide change from a thymine to a cytosine in exon 6 of the SHOX gene resulting in the abolition of the termination codon and an extension of the wild type protein by an additional 48 amino acids (PM4). The variant has been reported in a patient with Leri-Weill dyschondrosteosis and his similarly affected mother (PMID: 15356038) (PS4_supporting). The variant has been reported in dbSNP (rs137852559) but is absent from population databases (PM2). The SHOX gene is constraint for loss of function variants. The variant has not been reported in disease databases to date. The variant is paternally inherited. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.76

FATHMM_MKL

Uncertain

0.86

PhyloP100

4.4

Vest4

0.15

GERP RS

1.6

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over