12-57472038-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005269.3(GLI1):c.3298G>C(p.Glu1100Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,496,380 control chromosomes in the GnomAD database, including 331,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.67 ( 34873 hom., cov: 31)

Exomes 𝑓: 0.66 ( 296679 hom. )

Consequence

GLI1
NM_005269.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.39

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 links:

ARHGAP9 (HGNC:14130): (Rho GTPase activating protein 9) This gene encodes a member of the Rho-GAP family of GTPase activating proteins. The protein has substantial GAP activity towards several Rho-family GTPases in vitro, converting them to an inactive GDP-bound state. It is implicated in regulating adhesion of hematopoietic cells to the extracellular matrix. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ARHGAP9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5715231E-6).

BP6

Variant 12-57472038-G-C is Benign according to our data. Variant chr12-57472038-G-C is described in ClinVar as [Benign]. Clinvar id is 1285295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI1	NM_005269.3 link	c.3298G>C	p.Glu1100Gln	missense_variant	Exon 12 of 12	ENST00000228682.7	NP_005260.1	P08151-1
ARHGAP9	NM_032496.4 link	c.*479C>G		downstream_gene_variant		ENST00000393791.8	NP_115885.2	Q9BRR9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7 link	c.3298G>C	p.Glu1100Gln	missense_variant	Exon 12 of 12	1	NM_005269.3	ENSP00000228682.2		P08151-1
ARHGAP9	ENST00000393791.8 link	c.*479C>G		downstream_gene_variant		1	NM_032496.4	ENSP00000377380.3		Q9BRR9-2

Frequencies

GnomAD3 genomes

AF:

0.669

AC:

101637

AN:

151880

Hom.:

34843

Cov.:

show subpopulations

Gnomad AFR

AF:

0.772

Gnomad AMI

AF:

0.730

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.689

Gnomad EAS

AF:

0.391

Gnomad SAS

AF:

0.514

Gnomad FIN

AF:

0.565

Gnomad MID

AF:

0.799

Gnomad NFE

AF:

0.682

Gnomad OTH

AF:

0.674

GnomAD3 exomes

AF:

0.601

AC:

100771

AN:

167630

Hom.:

31946

AF XY:

0.606

AC XY:

54451

AN XY:

89868

show subpopulations

Gnomad AFR exome

AF:

0.773

Gnomad AMR exome

AF:

0.379

Gnomad ASJ exome

AF:

0.696

Gnomad EAS exome

AF:

0.363

Gnomad SAS exome

AF:

0.506

Gnomad FIN exome

AF:

0.564

Gnomad NFE exome

AF:

0.677

Gnomad OTH exome

AF:

0.641

GnomAD4 exome

AF:

0.659

AC:

886314

AN:

1344382

Hom.:

296679

Cov.:

AF XY:

0.657

AC XY:

432734

AN XY:

659090

show subpopulations

Gnomad4 AFR exome

AF:

0.780

Gnomad4 AMR exome

AF:

0.415

Gnomad4 ASJ exome

AF:

0.685

Gnomad4 EAS exome

AF:

0.456

Gnomad4 SAS exome

AF:

0.513

Gnomad4 FIN exome

AF:

0.568

Gnomad4 NFE exome

AF:

0.683

Gnomad4 OTH exome

AF:

0.646

GnomAD4 genome

AF:

0.669

AC:

101705

AN:

151998

Hom.:

34873

Cov.:

AF XY:

0.657

AC XY:

48801

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.772

Gnomad4 AMR

AF:

0.535

Gnomad4 ASJ

AF:

0.689

Gnomad4 EAS

AF:

0.391

Gnomad4 SAS

AF:

0.514

Gnomad4 FIN

AF:

0.565

Gnomad4 NFE

AF:

0.682

Gnomad4 OTH

AF:

0.671

Alfa

AF:

0.672

Hom.:

21351

Bravo

AF:

0.667

TwinsUK

AF:

0.693

AC:

2570

ALSPAC

AF:

0.684

AC:

2637

ESP6500AA

AF:

0.770

AC:

3394

ESP6500EA

AF:

0.682

AC:

5864

ExAC

AF:

0.597

AC:

71945

Asia WGS

AF:

0.502

AC:

1747

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polydactyly, postaxial, type A8

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polydactyly of a biphalangeal thumb

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.25

.;T;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.16

T;T;T;.

MetaRNN

Benign

0.0000016

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

.;N;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

0.28

N;N;N;N

REVEL

Benign

0.083

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.060

MPC

0.17

ClinPred

0.0020

GERP RS

4.7

Varity_R

0.068

gMVP

0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over