rs74536326

Positions:

chr7-42048700-G-A

Variant summary

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

The NM_000168.6(GLI3):c.474-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,603,260 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00068 ( 8 hom. )

Consequence

GLI3
NM_000168.6 splice_region, intron

Scores

Splicing: ADA: 0.0001710

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.323

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=-0.72).

BP6

Variant 7-42048700-G-A is Benign according to our data. Variant chr7-42048700-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 360255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000678 (986/1453976) while in subpopulation EAS AF= 0.0162 (640/39590). AF 95% confidence interval is 0.0151. There are 8 homozygotes in gnomad4_exome. There are 484 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6 linkuse as main transcript	c.474-4C>T		splice_region_variant, intron_variant		ENST00000395925.8	NP_000159.3	P10071

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8 linkuse as main transcript	c.474-4C>T		splice_region_variant, intron_variant		5	NM_000168.6	ENSP00000379258.3		P10071

Frequencies

GnomAD3 genomes

AF:

0.000463

AC:

AN:

149166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00174

Gnomad EAS

AF:

0.00939

Gnomad SAS

AF:

0.00153

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000888

Gnomad OTH

AF:

0.000992

GnomAD3 exomes

AF:

0.000970

AC:

240

AN:

247452

Hom.:

AF XY:

0.00102

AC XY:

137

AN XY:

133734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.00893

Gnomad SAS exome

AF:

0.00171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000678

AC:

986

AN:

1453976

Hom.:

Cov.:

AF XY:

0.000669

AC XY:

484

AN XY:

723630

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.0162

Gnomad4 SAS exome

AF:

0.00152

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.000698

GnomAD4 genome

AF:

0.000462

AC:

AN:

149284

Hom.:

Cov.:

AF XY:

0.000509

AC XY:

AN XY:

72648

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00174

Gnomad4 EAS

AF:

0.00941

Gnomad4 SAS

AF:

0.00153

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000888

Gnomad4 OTH

AF:

0.000981

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000397

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2023

- -

Greig cephalopolysyndactyly syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 06, 2020

- -

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

Aug 16, 2021

- -

Pallister-Hall syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Polydactyly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.4

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.070

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