NM_000168.6:c.368-19G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.405

Variant links:

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]

GLI3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 allele frequency = 0.00844 (1284/152212) while in subpopulation NFE AF= 0.0111 (752/68000). AF 95% confidence interval is 0.0104. There are 11 homozygotes in gnomad4. There are 601 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1284 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.368-19G>A		intron_variant	Intron 3 of 14	ENST00000395925.8	NP_000159.3	P10071

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8 link	c.368-19G>A		intron_variant	Intron 3 of 14	5	NM_000168.6	ENSP00000379258.3		P10071

Frequencies

GnomAD3 genomes

AF:

0.00845

AC:

1285

AN:

152094

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00943

AC XY:

1275

AN XY:

135200

show subpopulations

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.:

Cov.:

AF XY:

0.0104

AC XY:

6677

AN XY:

639508

show subpopulations

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.:

Cov.:

AF XY:

0.00807

AC XY:

601

AN XY:

74432

show subpopulations

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.:

Bravo

AF:

0.00857

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over