rs2228226

Positions:

• chr12-57472038-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005269.3(GLI1):​c.3298G>C​(p.Glu1100Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,496,380 control chromosomes in the GnomAD database, including 331,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.67 (34873 hom., cov: 31)
  • Exomes 𝑓: 0.66 (296679 hom.)
• Consequence: GLI1 NM_005269.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5715231E-6).
• BP6: Variant 12-57472038-G-C is Benign according to our data. Variant chr12-57472038-G-C is described in ClinVar as [Benign]. Clinvar id is 1285295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI1	NM_005269.3	c.3298G>C	p.Glu1100Gln	missense_variant	12/12	ENST00000228682.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI1	ENST00000228682.7	c.3298G>C	p.Glu1100Gln	missense_variant	12/12	1	NM_005269.3	P1
GLI1	ENST00000528467.1	c.3175G>C	p.Glu1059Gln	missense_variant	10/10	1
GLI1	ENST00000546141.5	c.3175G>C	p.Glu1059Gln	missense_variant	11/11	5
GLI1	ENST00000543426.5	c.2914G>C	p.Glu972Gln	missense_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101637 AN: 151880 Hom.: 34843 Cov.: 31

Gnomad AFR AF: 0.772

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.799

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.674

GnomAD3 exomes AF: 0.601 AC: 100771 AN: 167630 Hom.: 31946 AF XY: 0.606 AC XY: 54451 AN XY: 89868

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.696

Gnomad EAS exome AF: 0.363

Gnomad SAS exome AF: 0.506

Gnomad FIN exome AF: 0.564

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.659 AC: 886314 AN: 1344382 Hom.: 296679 Cov.: 30 AF XY: 0.657 AC XY: 432734 AN XY: 659090

Gnomad4 AFR exome AF: 0.780

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.685

Gnomad4 EAS exome AF: 0.456

Gnomad4 SAS exome AF: 0.513

Gnomad4 FIN exome AF: 0.568

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.646

GnomAD4 genome AF: 0.669 AC: 101705 AN: 151998 Hom.: 34873 Cov.: 31 AF XY: 0.657 AC XY: 48801 AN XY: 74282

Gnomad4 AFR AF: 0.772

Gnomad4 AMR AF: 0.535

Gnomad4 ASJ AF: 0.689

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.565

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.671

Alfa AF: 0.672 Hom.: 21351

Bravo AF: 0.667

TwinsUK AF: 0.693 AC: 2570

ALSPAC AF: 0.684 AC: 2637

ESP6500AA AF: 0.770 AC: 3394

ESP6500EA AF: 0.682 AC: 5864

ExAC AF: 0.597 AC: 71945

Asia WGS AF: 0.502 AC: 1747 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polydactyly, postaxial, type A8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Polydactyly of a biphalangeal thumb Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.25	.;T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.16	T;T;T;.
MetaRNN	Benign	0.0000016	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	.;N;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.28	N;N;N;N
REVEL	Benign	0.083
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.060
MPC		0.17
ClinPred		0.0020	T
GERP RS		4.7
Varity_R		0.068
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

LitVar

Other links and lift over

dbSNP: rs2228226; hg19: chr12-57865821; COSMIC: COSV57357806; COSMIC: COSV57357806;