rs35364414

chr7-41964464-G-A

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.4609C>T(p.Arg1537Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,614,054 control chromosomes in the GnomAD database, including 2,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1537H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (106 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2117 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 10.0

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=0.007484019).
• BP6: Variant 7-41964464-G-A is Benign according to our data. Variant chr7-41964464-G-A is described in ClinVar as [Benign]. Clinvar id is 255443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41964464-G-A is described in Lovd as [Benign]. Variant chr7-41964464-G-A 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	UniProt
GLI3	NM_000168.6	c.4609C>T	p.Arg1537Cys	missense_variant	15/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.4609C>T	p.Arg1537Cys	missense_variant	15/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5265 AN: 152196 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0430

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0372 AC: 9353 AN: 251380 Hom.: 220 AF XY: 0.0395 AC XY: 5373 AN XY: 135876

Gnomad AFR exome AF: 0.00831

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0458

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0503

Gnomad OTH exome AF: 0.0386

GnomAD4 exome AF: 0.0510 AC: 74501 AN: 1461740 Hom.: 2117 Cov.: 32 AF XY: 0.0510 AC XY: 37119 AN XY: 727186

Gnomad4 AFR exome AF: 0.00798

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0459

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0570

Gnomad4 OTH exome AF: 0.0473

GnomAD4 genome AF: 0.0345 AC: 5262 AN: 152314 Hom.: 106 Cov.: 32 AF XY: 0.0327 AC XY: 2432 AN XY: 74482

Gnomad4 AFR AF: 0.00998

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0427

Gnomad4 FIN AF: 0.0305

Gnomad4 NFE AF: 0.0531

Gnomad4 OTH AF: 0.0384

Alfa AF: 0.0482 Hom.: 309

Bravo AF: 0.0321

TwinsUK AF: 0.0577 AC: 214

ALSPAC AF: 0.0633 AC: 244

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0566 AC: 487

ExAC AF: 0.0367 AC: 4452

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0554

EpiControl AF: 0.0493

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	This variant is associated with the following publications: (PMID: 31139930) -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Greig cephalopolysyndactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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 13, 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	0.22
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Benign	0.28
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.048	D;.
Polyphen		1.0	D;.
Vest4		0.24
MPC		1.2
ClinPred		0.031	T
GERP RS		6.0
Varity_R		0.37
gMVP		0.64

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: rs35364414; hg19: chr7-42004062; COSMIC: COSV67887293;