dbSNP rs202182779: GLI3:p.Gly1001Cys (chr7-41966072-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000168.6(GLI3):c.3001G>T(p.Gly1001Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1001S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.253

Publications

3 publications found

Variant links:

Genes affected

GLI3 (HGNC:4319): (GLI family zinc finger 3) This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

GLI3 Gene-Disease associations (from GenCC):

Greig cephalopolysyndactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
Pallister-Hall syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
polydactyly, postaxial, type A1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
polysyndactyly 4
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
tibial hemimelia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
acrocallosal syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
postaxial polydactyly type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GLI3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.118621886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.3001G>T	p.Gly1001Cys	missense_variant	Exon 15 of 15	ENST00000395925.8	NP_000159.3	P10071

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8 link	c.3001G>T	p.Gly1001Cys	missense_variant	Exon 15 of 15	5	NM_000168.6	ENSP00000379258.3		P10071

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1419810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32704

American (AMR)

AF:

0.00

AC:

AN:

40918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.00

AC:

AN:

37976

South Asian (SAS)

AF:

0.00

AC:

AN:

83126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097236

Other (OTH)

AF:

0.0000169

AC:

AN:

59008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.5

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

0.25

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.4

D;.

REVEL

Benign

0.10

Sift

Benign

0.040

D;.

Sift4G

Benign

0.098

T;.

Polyphen

0.14

B;.

Vest4

0.32

MutPred

0.26

Loss of MoRF binding (P = 0.0791);.;

MVP

0.32

MPC

0.95

ClinPred

0.72

GERP RS

0.14

Varity_R

0.19

gMVP

0.33

Mutation Taster

=89/11

polymorphism

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over