dbSNP rs193921005: GLI1:p.Cys177Tyr (chr12-57465251-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005269.3(GLI1):c.530G>A(p.Cys177Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

GLI1
NM_005269.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.71

Publications

2 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28502858).

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	UniProt
GLI1	NM_005269.3	MANE Select	c.530G>A	p.Cys177Tyr	missense	Exon 5 of 12	NP_005260.1	P08151-1
GLI1	NM_001167609.2		c.407G>A	p.Cys136Tyr	missense	Exon 4 of 11	NP_001161081.1	P08151-2
GLI1	NM_001160045.2		c.146G>A	p.Cys49Tyr	missense	Exon 3 of 10	NP_001153517.1	P08151-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLI1	ENST00000228682.7	TSL:1 MANE Select	c.530G>A	p.Cys177Tyr	missense	Exon 5 of 12	ENSP00000228682.2	P08151-1
GLI1	ENST00000528467.1	TSL:1	c.407G>A	p.Cys136Tyr	missense	Exon 3 of 10	ENSP00000434408.1	P08151-2
GLI1	ENST00000546141.5	TSL:5	c.407G>A	p.Cys136Tyr	missense	Exon 4 of 11	ENSP00000441006.1	P08151-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.0084

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.77

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.70

M_CAP

Benign

0.043

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.0

PhyloP100

2.7

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

REVEL

Benign

0.068

Sift

Uncertain

0.0040

Sift4G

Benign

0.16

Polyphen

0.0010

Vest4

0.58

MutPred

0.41

Gain of catalytic residue at G172 (P = 0.01)

MVP

0.77

MPC

0.80

ClinPred

0.80

GERP RS

2.7

Varity_R

0.34

gMVP

0.40

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over