ENST00000381575.6:c.657G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000381575.6(SHOX):c.657G>A(p.Pro219Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 384,448 control chromosomes in the GnomAD database, including 83,240 homozygotes. There are 135,716 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37556 hom., 50134 hem., cov: 23)

Exomes 𝑓: 0.61 ( 45684 hom. 85582 hem. )

Consequence

SHOX
ENST00000381575.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.07

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=-0.87).

BP6

Variant X-658808-G-A is Benign according to our data. Variant chrX-658808-G-A is described in ClinVar as Benign. ClinVar VariationId is 586580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_006883.2 link	c.657G>A	p.Pro219Pro	synonymous_variant	Exon 6 of 6		NP_006874.1	O15266-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000381575.6 link	c.657G>A	p.Pro219Pro	synonymous_variant	Exon 5 of 5	1		ENSP00000370987.1		O15266-2
SHOX	ENST00000334060.8 link	c.657G>A	p.Pro219Pro	synonymous_variant	Exon 6 of 6	5		ENSP00000335505.3		O15266-2

Frequencies

GnomAD3 genomes

AF:

0.704

AC:

103690

AN:

147328

Hom.:

37509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.892

Gnomad AMI

AF:

0.641

Gnomad AMR

AF:

0.630

Gnomad ASJ

AF:

0.574

Gnomad EAS

AF:

0.734

Gnomad SAS

AF:

0.696

Gnomad FIN

AF:

0.570

Gnomad MID

AF:

0.710

Gnomad NFE

AF:

0.633

Gnomad OTH

AF:

0.676

GnomAD2 exomes

AF:

0.602

AC:

56209

AN:

93302

AF XY:

0.609

show subpopulations

Gnomad AFR exome

AF:

0.857

Gnomad AMR exome

AF:

0.554

Gnomad ASJ exome

AF:

0.548

Gnomad EAS exome

AF:

0.660

Gnomad FIN exome

AF:

0.537

Gnomad NFE exome

AF:

0.590

Gnomad OTH exome

AF:

0.581

GnomAD4 exome

AF:

0.612

AC:

145133

AN:

237004

Hom.:

45684

Cov.:

AF XY:

0.622

AC XY:

85582

AN XY:

137582

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.866

AC:

4546

AN:

5250

American (AMR)

AF:

0.554

AC:

12204

AN:

22024

Ashkenazi Jewish (ASJ)

AF:

0.541

AC:

4813

AN:

8894

East Asian (EAS)

AF:

0.683

AC:

3957

AN:

5796

South Asian (SAS)

AF:

0.674

AC:

31980

AN:

47418

European-Finnish (FIN)

AF:

0.540

AC:

5700

AN:

10556

Middle Eastern (MID)

AF:

0.678

AC:

568

AN:

838

European-Non Finnish (NFE)

AF:

0.595

AC:

74671

AN:

125432

Other (OTH)

AF:

0.620

AC:

6694

AN:

10796

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.384

Heterozygous variant carriers

2052

4104

6157

8209

10261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

336

672

1008

1344

1680

<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:

0.704

AC:

103795

AN:

147444

Hom.:

37556

Cov.:

AF XY:

0.701

AC XY:

50134

AN XY:

71512

show subpopulations

African (AFR)

AF:

0.892

AC:

35824

AN:

40168

American (AMR)

AF:

0.630

AC:

9249

AN:

14692

Ashkenazi Jewish (ASJ)

AF:

0.574

AC:

1978

AN:

3444

East Asian (EAS)

AF:

0.734

AC:

3579

AN:

4874

South Asian (SAS)

AF:

0.696

AC:

3222

AN:

4632

European-Finnish (FIN)

AF:

0.570

AC:

5309

AN:

9314

Middle Eastern (MID)

AF:

0.704

AC:

200

AN:

284

European-Non Finnish (NFE)

AF:

0.633

AC:

42482

AN:

67106

Other (OTH)

AF:

0.677

AC:

1378

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1353

2706

4058

5411

6764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.713

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 07, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 06, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

SHOX-related disorder

Benign:1

Feb 15, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.46

(source)

DANN

Benign

0.63

PhyloP100

-1.1

Splicing

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