NM_000168.6:c.*3004G>A

Variant names:

• chr7-41961326-C-T
• rs3735361
• NM_000168.6:c.*3004G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000168.6(GLI3):​c.*3004G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,342 control chromosomes in the GnomAD database, including 7,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (7200 hom., cov: 33)
  • Exomes 𝑓: 0.34 (17 hom.)
• Consequence: GLI3 NM_000168.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.637
• Publications: 16 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, G2P
• Pallister-Hall syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 7-41961326-C-T is Benign according to our data. Variant chr7-41961326-C-T is described in ClinVar as Benign. ClinVar VariationId is 360161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000168.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	NM_000168.6	MANE Select	c.*3004G>A		3_prime_UTR	Exon 15 of 15	NP_000159.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	ENST00000395925.8	TSL:5 MANE Select	c.*3004G>A		3_prime_UTR	Exon 15 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.*3004G>A		3_prime_UTR	Exon 15 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.*3004G>A		3_prime_UTR	Exon 15 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42207 AN: 151894 Hom.: 7194 Cov.: 33

Gnomad AFR AF: 0.0829

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.290

GnomAD4 exome AF: 0.342 AC: 113 AN: 330 Hom.: 17 Cov.: 0 AF XY: 0.328 AC XY: 67 AN XY: 204

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.343 AC: 109 AN: 318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.375 AC: 3 AN: 8

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.278 AC: 42237 AN: 152012 Hom.: 7200 Cov.: 33 AF XY: 0.282 AC XY: 20917 AN XY: 74286

African (AFR) AF: 0.0829 AC: 3440 AN: 41510

American (AMR) AF: 0.343 AC: 5242 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1225 AN: 3464

East Asian (EAS) AF: 0.588 AC: 3034 AN: 5156

South Asian (SAS) AF: 0.348 AC: 1674 AN: 4816

European-Finnish (FIN) AF: 0.336 AC: 3541 AN: 10550

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23145 AN: 67922

Other (OTH) AF: 0.298 AC: 628 AN: 2110

Alfa AF: 0.310 Hom.: 16881

Bravo AF: 0.270

Asia WGS AF: 0.452 AC: 1572 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	-	1	Pallister-Hall syndrome (1)
-	-	1	Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.8
DANN	Benign	0.66
PhyloP100		0.64
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: rs3735361; hg19: chr7-42000924;