7-41961971-TA-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000168.6(GLI3):c.*2358del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 136,184 control chromosomes in the GnomAD database, including 65 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.030 (65 hom., cov: 32)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: GLI3 NM_000168.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.972

Genes affected

GLI3 (HGNC:4319): (GLI family zinc finger 3) This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest population allele frequency = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.*2358del		3_prime_UTR_variant	15/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.*2358del		3_prime_UTR_variant	15/15	5	NM_000168.6	P1
GLI3	ENST00000677288.1	c.*2358del		3_prime_UTR_variant	14/14
GLI3	ENST00000677605.1	c.*2358del		3_prime_UTR_variant	15/15			P1
GLI3	ENST00000678429.1	c.*2358del		3_prime_UTR_variant	15/15			P1

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4097 AN: 136108 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0133

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00313

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.0140

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0243

GnomAD4 exome AF: 0.167 AC: 1 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.0301 AC: 4101 AN: 136178 Hom.: 65 Cov.: 32 AF XY: 0.0302 AC XY: 1987 AN XY: 65780

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.00335

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0511

Gnomad4 NFE AF: 0.0389

Gnomad4 OTH AF: 0.0241

Bravo AF: 0.0250

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Greig cephalopolysyndactyly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Polydactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pallister-Hall syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144064690; hg19: chr7-42001569;