rs34089404

Variant names:

• chr7-41965002-G-A
• rs34089404
• NM_000168.6:c.4071C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-41965002-G-A
• chr7-41965002-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000168.6(GLI3):​c.4071C>T​(p.Tyr1357Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 1,613,802 control chromosomes in the GnomAD database, including 6,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (399 hom., cov: 33)
  • Exomes 𝑓: 0.085 (5768 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.283

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-41965002-G-A is Benign according to our data. Variant chr7-41965002-G-A is described in ClinVar as [Benign]. Clinvar id is 255442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41965002-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.283 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.4071C>T	p.Tyr1357Tyr	synonymous_variant	Exon 15 of 15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.4071C>T	p.Tyr1357Tyr	synonymous_variant	Exon 15 of 15	5	NM_000168.6	ENSP00000379258.3

Frequencies

GnomAD3 genomes AF: 0.0702 AC: 10683 AN: 152158 Hom.: 398 Cov.: 33

Gnomad AFR AF: 0.0586

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.00329

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0862

Gnomad OTH AF: 0.0761

GnomAD3 exomes AF: 0.0680 AC: 17070 AN: 250908 Hom.: 711 AF XY: 0.0714 AC XY: 9694 AN XY: 135820

Gnomad AFR exome AF: 0.0577

Gnomad AMR exome AF: 0.0424

Gnomad ASJ exome AF: 0.0879

Gnomad EAS exome AF: 0.00185

Gnomad SAS exome AF: 0.0913

Gnomad FIN exome AF: 0.0522

Gnomad NFE exome AF: 0.0826

Gnomad OTH exome AF: 0.0757

GnomAD4 exome AF: 0.0855 AC: 124956 AN: 1461526 Hom.: 5768 Cov.: 34 AF XY: 0.0857 AC XY: 62338 AN XY: 727076

Gnomad4 AFR exome AF: 0.0570

Gnomad4 AMR exome AF: 0.0445

Gnomad4 ASJ exome AF: 0.0871

Gnomad4 EAS exome AF: 0.00209

Gnomad4 SAS exome AF: 0.0890

Gnomad4 FIN exome AF: 0.0534

Gnomad4 NFE exome AF: 0.0924

Gnomad4 OTH exome AF: 0.0823

GnomAD4 genome AF: 0.0702 AC: 10695 AN: 152276 Hom.: 399 Cov.: 33 AF XY: 0.0663 AC XY: 4934 AN XY: 74444

Gnomad4 AFR AF: 0.0588

Gnomad4 AMR AF: 0.0566

Gnomad4 ASJ AF: 0.0882

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.0856

Gnomad4 FIN AF: 0.0485

Gnomad4 NFE AF: 0.0862

Gnomad4 OTH AF: 0.0762

Alfa AF: 0.0780 Hom.: 277

Bravo AF: 0.0692

Asia WGS AF: 0.0590 AC: 204 AN: 3478

EpiCase AF: 0.0880

EpiControl AF: 0.0831

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Greig cephalopolysyndactyly syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polydactyly Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.85
CADD	Benign	0.71
DANN	Benign	0.41

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: rs34089404; hg19: chr7-42004600; COSMIC: COSV67890010;