12-57467043-T-C

Variant names:

• chr12-57467043-T-C
• rs4760259
• NM_005269.3:c.913-290T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005269.3(GLI1):​c.913-290T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 152,032 control chromosomes in the GnomAD database, including 32,797 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.65 (32797 hom., cov: 31)
• Consequence: GLI1 NM_005269.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.997
• Publications: 28 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]

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI1	NM_005269.3	c.913-290T>C		intron_variant	Intron 8 of 11	ENST00000228682.7	NP_005260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7	c.913-290T>C		intron_variant	Intron 8 of 11	1	NM_005269.3	ENSP00000228682.2
GLI1	ENST00000528467.1	c.790-290T>C		intron_variant	Intron 6 of 9	1		ENSP00000434408.1
GLI1	ENST00000546141.5	c.790-290T>C		intron_variant	Intron 7 of 10	5		ENSP00000441006.1
GLI1	ENST00000543426.5	c.529-290T>C		intron_variant	Intron 6 of 9	5		ENSP00000437607.1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98640 AN: 151914 Hom.: 32775 Cov.: 31

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.654

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.649 AC: 98701 AN: 152032 Hom.: 32797 Cov.: 31 AF XY: 0.637 AC XY: 47338 AN XY: 74314

African (AFR) AF: 0.714 AC: 29620 AN: 41466

American (AMR) AF: 0.522 AC: 7979 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2396 AN: 3464

East Asian (EAS) AF: 0.337 AC: 1742 AN: 5172

South Asian (SAS) AF: 0.518 AC: 2495 AN: 4818

European-Finnish (FIN) AF: 0.553 AC: 5831 AN: 10544

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46377 AN: 67978

Other (OTH) AF: 0.651 AC: 1368 AN: 2102

Alfa AF: 0.672 Hom.: 144771

Bravo AF: 0.644

Asia WGS AF: 0.471 AC: 1640 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.24
DANN	Benign	0.31
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4760259; hg19: chr12-57860826;