Genetic Variant GLI3:c.679+40C>A (chr7-42048451-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000168.6(GLI3):c.679+40C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,312,340 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 29)

Exomes 𝑓: 0.0018 ( 1 hom. )

Consequence

GLI3
NM_000168.6 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.54

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 7-42048451-G-T is Benign according to our data. Variant chr7-42048451-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255447.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00149 (226/151946) while in subpopulation NFE AF= 0.00228 (155/67974). AF 95% confidence interval is 0.00199. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High AC in GnomAd4 at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.679+40C>A		intron_variant	Intron 5 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.679+40C>A		intron_variant	Intron 5 of 14	5	NM_000168.6	ENSP00000379258.3		P10071

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

227

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000460

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00149

AC:

373

AN:

250496

Hom.:

AF XY:

0.00155

AC XY:

210

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00875

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00266

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00177

AC:

2053

AN:

1160394

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1057

AN XY:

592258

show subpopulations

Gnomad4 AFR exome

AF:

0.000399

Gnomad4 AMR exome

AF:

0.000316

Gnomad4 ASJ exome

AF:

0.00872

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000237

Gnomad4 FIN exome

AF:

0.00232

Gnomad4 NFE exome

AF:

0.00189

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00149

AC:

226

AN:

151946

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.000459

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00189

Gnomad4 NFE

AF:

0.00228

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00214

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.27

DANN

Benign

0.81

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

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