rs35961850

chr7-42040166-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000168.6(GLI3):c.900C>T(p.Ser300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0864 in 1,613,370 control chromosomes in the GnomAD database, including 6,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (536 hom., cov: 33)
  • Exomes 𝑓: 0.088 (6398 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.809

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-42040166-G-A is Benign according to our data. Variant chr7-42040166-G-A is described in ClinVar as [Benign]. Clinvar id is 255451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42040166-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.809 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.900C>T	p.Ser300=	synonymous_variant	7/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.900C>T	p.Ser300=	synonymous_variant	7/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.0740 AC: 11249 AN: 152094 Hom.: 536 Cov.: 33

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0557

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0564

GnomAD3 exomes AF: 0.0693 AC: 17414 AN: 251442 Hom.: 800 AF XY: 0.0704 AC XY: 9564 AN XY: 135884

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.0348

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0282

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0989

Gnomad OTH exome AF: 0.0663

GnomAD4 exome AF: 0.0877 AC: 128178 AN: 1461158 Hom.: 6398 Cov.: 32 AF XY: 0.0864 AC XY: 62843 AN XY: 726952

Gnomad4 AFR exome AF: 0.0338

Gnomad4 AMR exome AF: 0.0371

Gnomad4 ASJ exome AF: 0.0602

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.0992

Gnomad4 OTH exome AF: 0.0750

GnomAD4 genome AF: 0.0739 AC: 11256 AN: 152212 Hom.: 536 Cov.: 33 AF XY: 0.0731 AC XY: 5444 AN XY: 74428

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.0578

Gnomad4 ASJ AF: 0.0557

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0923 Hom.: 407

Bravo AF: 0.0642

Asia WGS AF: 0.0220 AC: 79 AN: 3478

EpiCase AF: 0.0913

EpiControl AF: 0.0861

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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome;C1868111:Polysyndactyly 4;C4282400:Polydactyly, postaxial, type A1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 02, 2022

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	3.3
Dann	Benign	0.75

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

Other links and lift over

dbSNP: rs35961850; hg19: chr7-42079765; COSMIC: COSV67885640;