12-57466263-C-T

Variant names:

• chr12-57466263-C-T
• rs7973381
• NM_005269.3:c.786C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_005269.3(GLI1):​c.786C>T​(p.His262His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,368 control chromosomes in the GnomAD database, including 1,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.056 (491 hom., cov: 32)
  • Exomes 𝑓: 0.023 (817 hom.)
• Consequence: GLI1 NM_005269.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.84

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-57466263-C-T is Benign according to our data. Variant chr12-57466263-C-T is described in ClinVar as [Benign]. Clinvar id is 3056398.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI1	NM_005269.3	c.786C>T	p.His262His	synonymous_variant	Exon 8 of 12	ENST00000228682.7	NP_005260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7	c.786C>T	p.His262His	synonymous_variant	Exon 8 of 12	1	NM_005269.3	ENSP00000228682.2

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8565 AN: 152052 Hom.: 487 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0449

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0574

GnomAD3 exomes AF: 0.0322 AC: 8062 AN: 250590 Hom.: 317 AF XY: 0.0316 AC XY: 4287 AN XY: 135470

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0495

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0227 AC: 33231 AN: 1461198 Hom.: 817 Cov.: 32 AF XY: 0.0234 AC XY: 17037 AN XY: 726900

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.0238

Gnomad4 ASJ exome AF: 0.0476

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0481

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0564 AC: 8582 AN: 152170 Hom.: 491 Cov.: 32 AF XY: 0.0566 AC XY: 4207 AN XY: 74376

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0449

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.0267

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0568

Alfa AF: 0.0245 Hom.: 208

Bravo AF: 0.0622

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GLI1-related disorder Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.46
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7973381; hg19: chr12-57860046; COSMIC: COSV57359402; COSMIC: COSV57359402;