rs746391025

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000451.4(SHOX):c.870G>A(p.Leu290Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,496,816 control chromosomes in the GnomAD database, including 46 homozygotes. There are 1,678 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0099 ( 28 hom., 741 hem., cov: 33)

Exomes 𝑓: 0.0016 ( 18 hom. 937 hem. )

Consequence

SHOX
NM_000451.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.33

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant X-644627-G-A is Benign according to our data. Variant chrX-644627-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.33 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00992 (1510/152234) while in subpopulation AFR AF = 0.0307 (1277/41564). AF 95% confidence interval is 0.0293. There are 28 homozygotes in GnomAd4. There are 741 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4 link	c.870G>A	p.Leu290Leu	synonymous_variant	Exon 5 of 5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2 link	c.633+3540G>A		intron_variant	Intron 5 of 5		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SHOX	ENST00000686671.1 link	c.870G>A	p.Leu290Leu	synonymous_variant	Exon 5 of 5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6 link	c.633+3540G>A		intron_variant	Intron 4 of 4	1		ENSP00000370987.1
SHOX	ENST00000381578.6 link	c.870G>A	p.Leu290Leu	synonymous_variant	Exon 6 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060.8 link	c.633+3540G>A		intron_variant	Intron 5 of 5	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes

AF:

0.00987

AC:

1502

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00275

AC:

265

AN:

96440

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.0446

Gnomad AMR exome

AF:

0.00511

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000977

Gnomad OTH exome

AF:

0.00585

GnomAD4 exome

AF:

0.00156

AC:

2093

AN:

1344582

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

937

AN XY:

662750

show subpopulations

African (AFR)

AF:

0.0356

AC:

972

AN:

27268

American (AMR)

AF:

0.00484

AC:

152

AN:

31418

Ashkenazi Jewish (ASJ)

AF:

0.00697

AC:

166

AN:

23800

East Asian (EAS)

AF:

0.0000322

AC:

AN:

31098

South Asian (SAS)

AF:

0.0000930

AC:

AN:

75296

European-Finnish (FIN)

AF:

0.0000300

AC:

AN:

33362

Middle Eastern (MID)

AF:

0.00936

AC:

AN:

3952

European-Non Finnish (NFE)

AF:

0.000474

AC:

504

AN:

1062474

Other (OTH)

AF:

0.00452

AC:

253

AN:

55914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

130

260

391

521

651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00992

AC:

1510

AN:

152234

Hom.:

Cov.:

AF XY:

0.00996

AC XY:

741

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0307

AC:

1277

AN:

41564

American (AMR)

AF:

0.00797

AC:

122

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000633

AC:

AN:

67984

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

148

222

296

370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 04, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Dec 06, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.1

(source)

DANN

Benign

0.96

PhyloP100

2.3

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