Genetic Variant GLI1:p.His262His (chr12-57466263-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_005269.3(GLI1):c.786C>T(p.His262His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,368 control chromosomes in the GnomAD database, including 1,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.056 ( 491 hom., cov: 32)

Exomes 𝑓: 0.023 ( 817 hom. )

Consequence

GLI1
NM_005269.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.84

Publications

20 publications found

Variant links:

Genes affected

GLI1 (HGNC:4317): (GLI family zinc finger 1) This gene encodes a member of the Kruppel family of zinc finger proteins. The encoded transcription factor is activated by the sonic hedgehog signal transduction cascade and regulates stem cell proliferation. The activity and nuclear localization of this protein is negatively regulated by p53 in an inhibitory loop. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

GLI1 Gene-Disease associations (from GenCC):

Ellis-van Creveld syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
polydactyly of a biphalangeal thumb
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
postaxial polydactyly type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
polydactyly, postaxial, type A8
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GLI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 12-57466263-C-T is Benign according to our data. Variant chr12-57466263-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056398.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI1	NM_005269.3 link	c.786C>T	p.His262His	synonymous_variant	Exon 8 of 12	ENST00000228682.7	NP_005260.1	P08151-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7 link	c.786C>T	p.His262His	synonymous_variant	Exon 8 of 12	1	NM_005269.3	ENSP00000228682.2		P08151-1

Frequencies

GnomAD3 genomes

AF:

0.0563

AC:

8565

AN:

152052

Hom.:

487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.0333

Gnomad ASJ

AF:

0.0449

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0419

Gnomad FIN

AF:

0.0267

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0574

GnomAD2 exomes

AF:

0.0322

AC:

8062

AN:

250590

AF XY:

0.0316

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.0223

Gnomad ASJ exome

AF:

0.0490

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0277

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.0326

GnomAD4 exome

AF:

0.0227

AC:

33231

AN:

1461198

Hom.:

817

Cov.:

AF XY:

0.0234

AC XY:

17037

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.148

AC:

4964

AN:

33434

American (AMR)

AF:

0.0238

AC:

1061

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.0476

AC:

1240

AN:

26068

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39690

South Asian (SAS)

AF:

0.0481

AC:

4146

AN:

86178

European-Finnish (FIN)

AF:

0.0261

AC:

1392

AN:

53404

Middle Eastern (MID)

AF:

0.0609

AC:

351

AN:

5768

European-Non Finnish (NFE)

AF:

0.0163

AC:

18158

AN:

1111642

Other (OTH)

AF:

0.0317

AC:

1916

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1529

3059

4588

6118

7647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.0564

AC:

8582

AN:

152170

Hom.:

491

Cov.:

AF XY:

0.0566

AC XY:

4207

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.144

AC:

5986

AN:

41490

American (AMR)

AF:

0.0332

AC:

508

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0449

AC:

156

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.0419

AC:

202

AN:

4816

European-Finnish (FIN)

AF:

0.0267

AC:

283

AN:

10592

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0175

AC:

1187

AN:

68010

Other (OTH)

AF:

0.0568

AC:

120

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

390

781

1171

1562

1952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0292

Hom.:

625

Bravo

AF:

0.0622

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0218

EpiControl

AF:

0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GLI1-related disorder

Benign:1

Feb 21, 2019

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

-0.65

CADD

Benign

0.46

(source)

DANN

Benign

0.46

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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