rs79703713

Variant names:

• chr7-41965989-G-A
• rs79703713
• NM_000168.6:c.3084C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-41965989-G-A
• chr7-41965989-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000168.6(GLI3):​c.3084C>T​(p.Ser1028Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,604,450 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 32)
  • Exomes 𝑓: 0.019 (327 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.52
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-41965989-G-A is Benign according to our data. Variant chr7-41965989-G-A is described in ClinVar as Benign. ClinVar VariationId is 137486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0125 (1906/152296) while in subpopulation NFE AF = 0.0214 (1455/68002). AF 95% confidence interval is 0.0205. There are 21 homozygotes in GnomAd4. There are 789 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

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.3084C>T	p.Ser1028Ser	synonymous	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.3084C>T	p.Ser1028Ser	synonymous	Exon 15 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.3084C>T	p.Ser1028Ser	synonymous	Exon 15 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.3084C>T	p.Ser1028Ser	synonymous	Exon 15 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1908 AN: 152178 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00465

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0124 AC: 2914 AN: 234230 AF XY: 0.0123

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.00860

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00692

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0193 AC: 28019 AN: 1452154 Hom.: 327 Cov.: 34 AF XY: 0.0188 AC XY: 13550 AN XY: 722546

African (AFR) AF: 0.00374 AC: 125 AN: 33464

American (AMR) AF: 0.00683 AC: 305 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00936 AC: 244 AN: 26068

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39672

South Asian (SAS) AF: 0.00195 AC: 168 AN: 86152

European-Finnish (FIN) AF: 0.00698 AC: 314 AN: 44970

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5762

European-Non Finnish (NFE) AF: 0.0233 AC: 25945 AN: 1111164

Other (OTH) AF: 0.0139 AC: 837 AN: 60260

GnomAD4 genome AF: 0.0125 AC: 1906 AN: 152296 Hom.: 21 Cov.: 32 AF XY: 0.0106 AC XY: 789 AN XY: 74458

African (AFR) AF: 0.00462 AC: 192 AN: 41586

American (AMR) AF: 0.00915 AC: 140 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10624

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0214 AC: 1455 AN: 68002

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0191 Hom.: 58

Bravo AF: 0.0126

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0206

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	-	1	not provided (1)
-	-	1	Pallister-Hall syndrome (1)
-	-	1	Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.0
DANN	Benign	0.54
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs79703713; hg19: chr7-42005587; COSMIC: COSV67895404;