dbSNP rs2228226: GLI1:p.Glu1100Lys (chr12-57472038-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005269.3(GLI1):c.3298G>A(p.Glu1100Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000742 in 1,346,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. E1100Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

GLI1
NM_005269.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03622687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI1	NM_005269.3 link	c.3298G>A	p.Glu1100Lys	missense_variant	Exon 12 of 12	ENST00000228682.7	NP_005260.1	P08151-1
ARHGAP9	NM_032496.4 link	c.*479C>T		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>A	p.Glu1100Lys	missense_variant	Exon 12 of 12	1	NM_005269.3	ENSP00000228682.2		P08151-1
ARHGAP9	ENST00000393791.8 link	c.*479C>T		downstream_gene_variant		1	NM_032496.4	ENSP00000377380.3		Q9BRR9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.42e-7

AC:

AN:

1346828

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

660262

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.47e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.36

T;T;T;.

M_CAP

Benign

0.0039

MetaRNN

Benign

0.036

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.6

.;N;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

2.5

N;N;N;N

REVEL

Benign

0.086

Sift

Benign

0.33

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.18

MutPred

0.27

.;Gain of ubiquitination at E1100 (P = 0.0029);.;.;

MVP

0.36

MPC

0.19

ClinPred

0.38

GERP RS

4.7

Varity_R

0.042

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over