7-41965990-C-A

Position:

• chr7-41965990-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000168.6(GLI3):​c.3083G>T​(p.Ser1028Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,604,554 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1028S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 32)
  • Exomes 𝑓: 0.019 (328 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.31

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=0.0055089593).
• BP6: Variant 7-41965990-C-A is Benign according to our data. Variant chr7-41965990-C-A is described in ClinVar as [Benign]. Clinvar id is 137485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41965990-C-A is described in Lovd as [Benign]. Variant chr7-41965990-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1906/152264) while in subpopulation NFE AF= 0.0214 (1455/67990). AF 95% confidence interval is 0.0205. There are 21 homozygotes in gnomad4. There are 789 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1906 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6	c.3083G>T	p.Ser1028Ile	missense_variant	15/15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.3083G>T	p.Ser1028Ile	missense_variant	15/15	5	NM_000168.6	ENSP00000379258	P1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1908 AN: 152146 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00451

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0124 AC: 2906 AN: 234352 Hom.: 30 AF XY: 0.0123 AC XY: 1581 AN XY: 128670

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.00859

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00191

Gnomad FIN exome AF: 0.00671

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0193 AC: 28016 AN: 1452290 Hom.: 328 Cov.: 34 AF XY: 0.0187 AC XY: 13547 AN XY: 722602

Gnomad4 AFR exome AF: 0.00374

Gnomad4 AMR exome AF: 0.00683

Gnomad4 ASJ exome AF: 0.00936

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00691

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0125 AC: 1906 AN: 152264 Hom.: 21 Cov.: 32 AF XY: 0.0106 AC XY: 789 AN XY: 74448

Gnomad4 AFR AF: 0.00462

Gnomad4 AMR AF: 0.00914

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00451

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0195 Hom.: 22

Bravo AF: 0.0126

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.0193 AC: 166

ExAC AF: 0.0122 AC: 1475

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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	0.16
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.084	B;.
Vest4		0.033
MPC		0.53
ClinPred		0.065	T
GERP RS		0.26
Varity_R		0.27
gMVP		0.44

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: rs79049330; hg19: chr7-42005588; COSMIC: COSV67895407;