chr7-42048623-T-C

Position:

• chr7-42048623-T-C

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.547A>G​(p.Thr183Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,607,848 control chromosomes in the GnomAD database, including 266,873 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 0.63 (31372 hom., cov: 23)
  • Exomes 𝑓: 0.56 (235501 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.14

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=5.7114227E-7).
• BP6: Variant 7-42048623-T-C is Benign according to our data. Variant chr7-42048623-T-C is described in ClinVar as [Benign]. Clinvar id is 255446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42048623-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6	c.547A>G	p.Thr183Ala	missense_variant	5/15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.547A>G	p.Thr183Ala	missense_variant	5/15	5	NM_000168.6	ENSP00000379258	P1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 93747 AN: 147998 Hom.: 31332 Cov.: 23

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.565

GnomAD3 exomes AF: 0.544 AC: 136825 AN: 251422 Hom.: 39173 AF XY: 0.543 AC XY: 73768 AN XY: 135878

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.555

Gnomad SAS exome AF: 0.479

Gnomad FIN exome AF: 0.589

Gnomad NFE exome AF: 0.574

Gnomad OTH exome AF: 0.532

GnomAD4 exome AF: 0.563 AC: 822062 AN: 1459732 Hom.: 235501 Cov.: 37 AF XY: 0.560 AC XY: 407017 AN XY: 726358

Gnomad4 AFR exome AF: 0.873

Gnomad4 AMR exome AF: 0.368

Gnomad4 ASJ exome AF: 0.425

Gnomad4 EAS exome AF: 0.578

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.591

Gnomad4 NFE exome AF: 0.571

Gnomad4 OTH exome AF: 0.552

GnomAD4 genome AF: 0.634 AC: 93840 AN: 148116 Hom.: 31372 Cov.: 23 AF XY: 0.626 AC XY: 45019 AN XY: 71922

Gnomad4 AFR AF: 0.865

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.568

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.589

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.562

Alfa AF: 0.567 Hom.: 60989

Bravo AF: 0.633

TwinsUK AF: 0.578 AC: 2142

ALSPAC AF: 0.560 AC: 2157

ESP6500AA AF: 0.855 AC: 3767

ESP6500EA AF: 0.563 AC: 4841

ExAC AF: 0.563 AC: 68320

Asia WGS AF: 0.518 AC: 1807 AN: 3476

EpiCase AF: 0.559

EpiControl AF: 0.551

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 20, 2020	- -

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 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	0.050
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.23
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.027	T;T
MetaRNN	Benign	5.7e-7	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.1	N;.
REVEL	Benign	0.071
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.026
MPC		0.13
ClinPred		0.0017	T
GERP RS		3.2
Varity_R		0.040
gMVP		0.30

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: rs846266; hg19: chr7-42088222; COSMIC: COSV67884691; COSMIC: COSV67884691;