rs190600888

chr7-42023625-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000168.6(GLI3):c.1357-17C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,595,964 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (16 hom.)
• Consequence: GLI3 NM_000168.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.142

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-42023625-G-C is Benign according to our data. Variant chr7-42023625-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 255421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42023625-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 384 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.1357-17C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.1357-17C>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 384 AN: 151998 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00586

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00288 AC: 725 AN: 251414 Hom.: 5 AF XY: 0.00269 AC XY: 366 AN XY: 135884

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00734

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00827

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00242 AC: 3501 AN: 1443848 Hom.: 16 Cov.: 29 AF XY: 0.00246 AC XY: 1766 AN XY: 719336

Gnomad4 AFR exome AF: 0.000302

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00908

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.00791

Gnomad4 NFE exome AF: 0.00226

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00252 AC: 384 AN: 152116 Hom.: 1 Cov.: 33 AF XY: 0.00243 AC XY: 181 AN XY: 74362

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00586

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00452 Hom.: 1

Bravo AF: 0.00175

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2017	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

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GLI3: BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.8
Dann	Benign	0.43

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: rs190600888; hg19: chr7-42063224;