Genetic Variant NM_005269.3:c.2798G>C (chr12-57471538-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005269.3(GLI1):c.2798G>C(p.Gly933Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. G933D) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GLI1
NM_005269.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.925

Publications

62 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061097056).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005269.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLI1	NM_005269.3	MANE Select	c.2798G>C	p.Gly933Ala	missense	Exon 12 of 12	NP_005260.1
GLI1	NM_001167609.2		c.2675G>C	p.Gly892Ala	missense	Exon 11 of 11	NP_001161081.1
GLI1	NM_001160045.2		c.2414G>C	p.Gly805Ala	missense	Exon 10 of 10	NP_001153517.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLI1	ENST00000228682.7	TSL:1 MANE Select	c.2798G>C	p.Gly933Ala	missense	Exon 12 of 12	ENSP00000228682.2
GLI1	ENST00000528467.1	TSL:1	c.2675G>C	p.Gly892Ala	missense	Exon 10 of 10	ENSP00000434408.1
GLI1	ENST00000546141.5	TSL:5	c.2675G>C	p.Gly892Ala	missense	Exon 11 of 11	ENSP00000441006.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726654

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111568

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

85474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.27

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.67

M_CAP

Benign

0.0030

MetaRNN

Benign

0.061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.93

PrimateAI

Benign

0.33

PROVEAN

Benign

0.10

REVEL

Benign

0.033

Sift

Benign

0.083

Sift4G

Benign

0.55

Polyphen

0.044

Vest4

0.056

MutPred

0.21

Gain of catalytic residue at P928 (P = 0.0113)

MVP

0.37

MPC

0.19

ClinPred

0.088

GERP RS

0.56

Varity_R

0.049

gMVP

0.29

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over