7-41964300-C-A

Position:

• chr7-41964300-C-A

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.*30G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 1,604,184 control chromosomes in the GnomAD database, including 2,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (106 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2069 hom.)
• Consequence: GLI3 NM_000168.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.190

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 (BayesDel_noAF=-0.84).
• BP6: Variant 7-41964300-C-A is Benign according to our data. Variant chr7-41964300-C-A is described in ClinVar as [Benign]. Clinvar id is 255413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41964300-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6	c.*30G>T		3_prime_UTR_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.*30G>T		3_prime_UTR_variant	15/15	5	NM_000168.6	ENSP00000379258	P1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5315 AN: 152198 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0387

GnomAD3 exomes AF: 0.0372 AC: 9323 AN: 250612 Hom.: 213 AF XY: 0.0395 AC XY: 5360 AN XY: 135612

Gnomad AFR exome AF: 0.00965

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0431

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0456

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0504 AC: 73199 AN: 1451870 Hom.: 2069 Cov.: 28 AF XY: 0.0506 AC XY: 36546 AN XY: 722898

Gnomad4 AFR exome AF: 0.00981

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0421

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0456

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0563

Gnomad4 OTH exome AF: 0.0470

GnomAD4 genome AF: 0.0349 AC: 5313 AN: 152314 Hom.: 106 Cov.: 32 AF XY: 0.0330 AC XY: 2455 AN XY: 74462

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.0282

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0427

Gnomad4 FIN AF: 0.0305

Gnomad4 NFE AF: 0.0530

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0453 Hom.: 52

Bravo AF: 0.0326

Asia WGS AF: 0.0260 AC: 90 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Jul 15, 2018

- -

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.49
DANN	Benign	0.62

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: rs77886553; hg19: chr7-42003898;