rs35280470

Positions:

• chr7-41965066-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000168.6(GLI3):​c.4007G>A​(p.Gly1336Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,613,792 control chromosomes in the GnomAD database, including 2,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (103 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2042 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0960

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 (MetaRNN=0.002038449).
• BP6: Variant 7-41965066-C-T is Benign according to our data. Variant chr7-41965066-C-T is described in ClinVar as [Benign]. Clinvar id is 255440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41965066-C-T is described in Lovd as [Benign]. Variant chr7-41965066-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6	c.4007G>A	p.Gly1336Glu	missense_variant	15/15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.4007G>A	p.Gly1336Glu	missense_variant	15/15	5	NM_000168.6	ENSP00000379258	P1

Frequencies

GnomAD3 genomes AF: 0.0340 AC: 5172 AN: 152194 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0353 AC: 8849 AN: 250488 Hom.: 198 AF XY: 0.0369 AC XY: 5012 AN XY: 135700

Gnomad AFR exome AF: 0.00845

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0433

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0312

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0372

GnomAD4 exome AF: 0.0501 AC: 73164 AN: 1461480 Hom.: 2042 Cov.: 34 AF XY: 0.0497 AC XY: 36167 AN XY: 727054

Gnomad4 AFR exome AF: 0.00797

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0315

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0570

Gnomad4 OTH exome AF: 0.0459

GnomAD4 genome AF: 0.0339 AC: 5169 AN: 152312 Hom.: 103 Cov.: 32 AF XY: 0.0318 AC XY: 2366 AN XY: 74468

Gnomad4 AFR AF: 0.00998

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0246

Gnomad4 FIN AF: 0.0304

Gnomad4 NFE AF: 0.0530

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0485 Hom.: 180

Bravo AF: 0.0321

TwinsUK AF: 0.0558 AC: 207

ALSPAC AF: 0.0610 AC: 235

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0555 AC: 477

ExAC AF: 0.0345 AC: 4188

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0555

EpiControl AF: 0.0490

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Greig cephalopolysyndactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pallister-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.46	N;.
REVEL	Benign	0.027
Sift	Benign	0.12	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0040	B;.
Vest4		0.058
MPC		0.38
ClinPred		0.0035	T
GERP RS		2.4
Varity_R		0.037
gMVP		0.33

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: rs35280470; hg19: chr7-42004664; COSMIC: COSV67890017;