12-57472038-G-C

Variant names:

• chr12-57472038-G-C
• rs2228226
• NM_005269.3:c.3298G>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 64 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GLI1	NM_005269.3	c.3298G>C	p.Glu1100Gln	missense_variant	Exon 12 of 12	ENST00000228682.7	NP_005260.1
ARHGAP9	NM_032496.4	c.*479C>G		downstream_gene_variant		ENST00000393791.8	NP_115885.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7	c.3298G>C	p.Glu1100Gln	missense_variant	Exon 12 of 12	1	NM_005269.3	ENSP00000228682.2
ARHGAP9	ENST00000393791.8	c.*479C>G		downstream_gene_variant		1	NM_032496.4	ENSP00000377380.3

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

GnomAD2 exomes AF: 0.601 AC: 100771 AN: 167630 AF XY: 0.606

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 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

African (AFR) AF: 0.780 AC: 22573 AN: 28956

American (AMR) AF: 0.415 AC: 10827 AN: 26066

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 13763 AN: 20084

East Asian (EAS) AF: 0.456 AC: 16533 AN: 36220

South Asian (SAS) AF: 0.513 AC: 35212 AN: 68604

European-Finnish (FIN) AF: 0.568 AC: 28513 AN: 50174

Middle Eastern (MID) AF: 0.749 AC: 3963 AN: 5290

European-Non Finnish (NFE) AF: 0.683 AC: 719341 AN: 1053892

Other (OTH) AF: 0.646 AC: 35589 AN: 55096

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

African (AFR) AF: 0.772 AC: 32013 AN: 41468

American (AMR) AF: 0.535 AC: 8169 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2391 AN: 3472

East Asian (EAS) AF: 0.391 AC: 2012 AN: 5150

South Asian (SAS) AF: 0.514 AC: 2478 AN: 4824

European-Finnish (FIN) AF: 0.565 AC: 5953 AN: 10542

Middle Eastern (MID) AF: 0.788 AC: 230 AN: 292

European-Non Finnish (NFE) AF: 0.682 AC: 46377 AN: 67958

Other (OTH) AF: 0.671 AC: 1416 AN: 2110

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polydactyly of a biphalangeal thumb Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.
PhyloP100		1.4
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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