dbSNP rs115463742: GLI3:c.2104-50C>T (chr7-41967973-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000168.6(GLI3):c.2104-50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000739 in 1,420,906 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

GLI3
NM_000168.6 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.158

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=-0.8).

BP6

Variant 7-41967973-G-A is Benign according to our data. Variant chr7-41967973-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00368 (561/152328) while in subpopulation AFR AF= 0.013 (539/41570). AF 95% confidence interval is 0.0121. There are 3 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 561 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.2104-50C>T		intron_variant	Intron 13 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.2104-50C>T		intron_variant	Intron 13 of 14	5	NM_000168.6	ENSP00000379258.3		P10071

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

561

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000915

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000848

AC:

212

AN:

249928

Hom.:

AF XY:

0.000666

AC XY:

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.0122

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000385

AC:

489

AN:

1268578

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

212

AN XY:

641652

show subpopulations

Gnomad4 AFR exome

AF:

0.0146

Gnomad4 AMR exome

AF:

0.000292

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000365

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000107

Gnomad4 OTH exome

AF:

0.000706

GnomAD4 genome

AF:

0.00368

AC:

561

AN:

152328

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

267

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0130

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00382

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided

Benign:1

Jan 22, 2021

GeneDx

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

-0.80

CADD

Benign

4.7

DANN

Benign

0.71

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