rs749355015

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000451.4(SHOX):c.*41C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,396,558 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,019 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0048 ( 7 hom., 371 hem., cov: 33)

Exomes 𝑓: 0.0011 ( 8 hom. 648 hem. )

Consequence

SHOX
NM_000451.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.329

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0048 (731/152224) while in subpopulation AFR AF = 0.0147 (609/41518). AF 95% confidence interval is 0.0137. There are 7 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 7 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4 link	c.*41C>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2 link	c.633+3590C>A		intron_variant	Intron 5 of 5		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SHOX	ENST00000686671.1 link	c.*41C>A	3_prime_UTR_variant	Exon 5 of 5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6 link	c.633+3590C>A	intron_variant	Intron 4 of 4	1		ENSP00000370987.1
SHOX	ENST00000381578.6 link	c.*41C>A	3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060.8 link	c.633+3590C>A	intron_variant	Intron 5 of 5	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes

AF:

0.00477

AC:

725

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00182

AC:

AN:

13208

AF XY:

0.00230

show subpopulations

Gnomad AFR exome

AF:

0.0289

Gnomad AMR exome

AF:

0.00308

Gnomad ASJ exome

AF:

0.00372

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000657

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00111

AC:

1376

AN:

1244334

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

648

AN XY:

607386

show subpopulations

African (AFR)

AF:

0.0181

AC:

440

AN:

24284

American (AMR)

AF:

0.00263

AC:

AN:

12904

Ashkenazi Jewish (ASJ)

AF:

0.000686

AC:

AN:

17492

East Asian (EAS)

AF:

0.0000352

AC:

AN:

28394

South Asian (SAS)

AF:

0.000279

AC:

AN:

57430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30114

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

3526

European-Non Finnish (NFE)

AF:

0.000719

AC:

732

AN:

1018780

Other (OTH)

AF:

0.00251

AC:

129

AN:

51410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00480

AC:

731

AN:

152224

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

371

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0147

AC:

609

AN:

41518

American (AMR)

AF:

0.00412

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68000

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Bravo

AF:

0.00553

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

SHOX-related short stature

Uncertain:1

Mar 03, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.1

(source)

DANN

Benign

0.42

PhyloP100

0.33

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over