rs145419251

chr7-41964563-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000168.6(GLI3):c.4510A>C(p.Ile1504Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00218 in 1,614,018 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (60 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.16

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046133995).
• BP6: Variant 7-41964563-T-G is Benign according to our data. Variant chr7-41964563-T-G is described in ClinVar as [Benign]. Clinvar id is 360223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 591 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.4510A>C	p.Ile1504Leu	missense_variant	15/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.4510A>C	p.Ile1504Leu	missense_variant	15/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152158 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00486 AC: 1222 AN: 251484 Hom.: 32 AF XY: 0.00470 AC XY: 639 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0510

Gnomad NFE exome AF: 0.000835

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00200 AC: 2922 AN: 1461742 Hom.: 60 Cov.: 32 AF XY: 0.00191 AC XY: 1389 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0493

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00388 AC: 591 AN: 152276 Hom.: 12 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0522

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000415 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00376 AC: 456

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2023

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2022

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	0.037
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.074
Sift	Benign	0.13	T;.
Sift4G	Benign	0.29	T;.
Polyphen		0.018	B;.
Vest4		0.64
MVP		0.58
MPC		0.97
ClinPred		0.060	T
GERP RS		5.9
Varity_R		0.31
gMVP		0.23

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: rs145419251; hg19: chr7-42004161;