rs114814747

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374353.1(GLI2):c.4507G>A(p.Asp1503Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,798 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1503E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0094 ( 16 hom., cov: 32)

Exomes 𝑓: 0.013 ( 137 hom. )

Consequence

GLI2
NM_001374353.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:12

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

GLI2 (HGNC:4318): (GLI family zinc finger 2) This gene encodes a protein which belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. The encoded protein is associated with several phenotypes- Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

GLI2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-120990474-T-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.008831322).

BP6

Variant 2-120990472-G-A is Benign according to our data. Variant chr2-120990472-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 37084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120990472-G-A is described in Lovd as [Likely_benign]. Variant chr2-120990472-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00944 (1434/151976) while in subpopulation NFE AF= 0.0144 (978/67928). AF 95% confidence interval is 0.0136. There are 16 homozygotes in gnomad4. There are 687 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1434 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI2	NM_001374353.1 link	c.4507G>A	p.Asp1503Asn	missense_variant	14/14	ENST00000361492.9	NP_001361282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI2	ENST00000361492.9 link	c.4507G>A	p.Asp1503Asn	missense_variant	14/14	1	NM_001374353.1	ENSP00000354586.5		A0A7I2PJA1

Frequencies

GnomAD3 genomes

AF:

0.00945

AC:

1435

AN:

151858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00264

Gnomad AMI

AF:

0.137

Gnomad AMR

AF:

0.00662

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00960

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.00674

GnomAD3 exomes

AF:

0.00935

AC:

2349

AN:

251144

Hom.:

AF XY:

0.00977

AC XY:

1327

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.00249

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.0128

AC:

18678

AN:

1461822

Hom.:

137

Cov.:

AF XY:

0.0128

AC XY:

9287

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00236

Gnomad4 AMR exome

AF:

0.00364

Gnomad4 ASJ exome

AF:

0.0104

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0117

Gnomad4 FIN exome

AF:

0.00358

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.0108

GnomAD4 genome

AF:

0.00944

AC:

1434

AN:

151976

Hom.:

Cov.:

AF XY:

0.00925

AC XY:

687

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00263

Gnomad4 AMR

AF:

0.00655

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00961

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0144

Gnomad4 OTH

AF:

0.00667

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00910

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0144

AC:

124

ExAC

AF:

0.0100

AC:

1220

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	GLI2: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	This variant is associated with the following publications: (PMID: 29165578, 21204792, 22967285) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Holoprosencephaly 9

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2015	- -

Partial androgen insensitivity syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

European Non-Finnish population allele frequency is 1.398% (rs114814747, 1841/128804 alleles, 11 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.2, this variant is classified as BENIGN. Following criteria are met: BA1 -

Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.43

MPC

0.60

ClinPred

0.026

GERP RS

5.0

Varity_R

0.66

gMVP

0.36

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