rs79879393

Positions:

• chr7-42076876-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000168.6(GLI3):​c.368-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,417,012 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (92 hom.)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.405

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-42076876-C-T is Benign according to our data. Variant chr7-42076876-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42076876-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0105 (13313/1264800) while in subpopulation NFE AF= 0.0113 (10568/932064). AF 95% confidence interval is 0.0112. There are 92 homozygotes in gnomad4_exome. There are 6677 alleles in male gnomad4_exome subpopulation. Median coverage is 19. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1284 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6	c.368-19G>A		intron_variant		ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.368-19G>A		intron_variant		5	NM_000168.6	ENSP00000379258.3

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1285 AN: 152094 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00956 AC: 2393 AN: 250190 Hom.: 28 AF XY: 0.00943 AC XY: 1275 AN XY: 135200

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.00659

Gnomad ASJ exome AF: 0.0521

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00292

Gnomad FIN exome AF: 0.00602

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0105 AC: 13313 AN: 1264800 Hom.: 92 Cov.: 19 AF XY: 0.0104 AC XY: 6677 AN XY: 639508

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00735

Gnomad4 ASJ exome AF: 0.0466

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00283

Gnomad4 FIN exome AF: 0.00587

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00844 AC: 1284 AN: 152212 Hom.: 11 Cov.: 32 AF XY: 0.00807 AC XY: 601 AN XY: 74432

Gnomad4 AFR AF: 0.00246

Gnomad4 AMR AF: 0.00968

Gnomad4 ASJ AF: 0.0473

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00726

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0144 Hom.: 8

Bravo AF: 0.00857

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome;C1868111:Polysyndactyly 4;C4282400:Polydactyly, postaxial, type A1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.23

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: rs79879393; hg19: chr7-42116475; COSMIC: COSV67894116;