chr7-41964300-C-A

Variant names:

• chr7-41964300-C-A
• rs77886553
• NM_000168.6:c.*30G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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 -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 VariationId is 255413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 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.*30G>T		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.*30G>T		3_prime_UTR	Exon 15 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.*30G>T		3_prime_UTR	Exon 15 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.*30G>T		3_prime_UTR	Exon 15 of 15	ENSP00000502957.1	P10071

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

GnomAD2 exomes AF: 0.0372 AC: 9323 AN: 250612 AF XY: 0.0395

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 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

African (AFR) AF: 0.00981 AC: 327 AN: 33328

American (AMR) AF: 0.0222 AC: 994 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 1097 AN: 26072

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39662

South Asian (SAS) AF: 0.0456 AC: 3915 AN: 85834

European-Finnish (FIN) AF: 0.0316 AC: 1688 AN: 53402

Middle Eastern (MID) AF: 0.0389 AC: 223 AN: 5740

European-Non Finnish (NFE) AF: 0.0563 AC: 62123 AN: 1103062

Other (OTH) AF: 0.0470 AC: 2822 AN: 60080

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

African (AFR) AF: 0.0112 AC: 464 AN: 41570

American (AMR) AF: 0.0282 AC: 432 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0427 AC: 206 AN: 4826

European-Finnish (FIN) AF: 0.0305 AC: 324 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0530 AC: 3606 AN: 68020

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0440 Hom.: 67

Bravo AF: 0.0326

Asia WGS AF: 0.0260 AC: 90 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Pallister-Hall syndrome (1)
-	-	1	Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.49
DANN	Benign	0.62
PhyloP100		-0.19
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: rs77886553; hg19: chr7-42003898; COSMIC: COSV107506048;