rs199956247

chr7-41972674-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000168.6(GLI3):c.1813-47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,521,380 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (9 hom.)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.36

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-41972674-C-T is Benign according to our data. Variant chr7-41972674-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255425.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00127 (1738/1369134) while in subpopulation MID AF= 0.0162 (91/5614). AF 95% confidence interval is 0.0135. There are 9 homozygotes in gnomad4_exome. There are 915 alleles in male gnomad4_exome subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High AC in GnomAd at 177 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.1813-47G>A		intron_variant		ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.1813-47G>A		intron_variant		5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00136 AC: 311 AN: 227858 Hom.: 0 AF XY: 0.00155 AC XY: 192 AN XY: 123892

Gnomad AFR exome AF: 0.000339

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00184

Gnomad FIN exome AF: 0.000265

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.00127 AC: 1738 AN: 1369134 Hom.: 9 Cov.: 23 AF XY: 0.00134 AC XY: 915 AN XY: 685338

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.000982

Gnomad4 ASJ exome AF: 0.00655

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00171

Gnomad4 FIN exome AF: 0.000305

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00165

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74448

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00206 Hom.: 1

Bravo AF: 0.00143

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.27
Dann	Benign	0.39

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: rs199956247; hg19: chr7-42012273;