7-42158961-C-T

Variant names:

• chr7-42158961-C-T
• rs3801210
• NM_000168.6:c.125-10493G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000168.6(GLI3):​c.125-10493G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 151,932 control chromosomes in the GnomAD database, including 7,240 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7240 hom., cov: 32)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134
• Publications: 6 publications found

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]

GLI3 Gene-Disease associations (from GenCC):

• Greig cephalopolysyndactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Pallister-Hall syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
• polydactyly, postaxial, type A1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• polysyndactyly 4

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• tibial hemimelia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acrocallosal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postaxial polydactyly type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.125-10493G>A		intron_variant	Intron 2 of 14	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.125-10493G>A		intron_variant	Intron 2 of 14	5	NM_000168.6	ENSP00000379258.3
GLI3	ENST00000677605.1	c.125-10493G>A		intron_variant	Intron 2 of 14			ENSP00000503743.1
GLI3	ENST00000678429.1	c.125-10493G>A		intron_variant	Intron 2 of 14			ENSP00000502957.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46401 AN: 151814 Hom.: 7231 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.310

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.306 AC: 46443 AN: 151932 Hom.: 7240 Cov.: 32 AF XY: 0.301 AC XY: 22341 AN XY: 74222

African (AFR) AF: 0.303 AC: 12536 AN: 41408

American (AMR) AF: 0.263 AC: 4018 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3468

East Asian (EAS) AF: 0.176 AC: 911 AN: 5174

South Asian (SAS) AF: 0.248 AC: 1195 AN: 4814

European-Finnish (FIN) AF: 0.299 AC: 3155 AN: 10558

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22464 AN: 67920

Other (OTH) AF: 0.309 AC: 652 AN: 2110

Alfa AF: 0.322 Hom.: 35018

Bravo AF: 0.306

Asia WGS AF: 0.229 AC: 795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.41
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3801210; hg19: chr7-42198560;