chr7-42040166-G-A

Variant names:

• chr7-42040166-G-A
• rs35961850
• NM_000168.6:c.900C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000168.6(GLI3):​c.900C>T​(p.Ser300Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0864 in 1,613,370 control chromosomes in the GnomAD database, including 6,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S300S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.074 (536 hom., cov: 33)
  • Exomes 𝑓: 0.088 (6398 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.809
• Publications: 12 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-42040166-G-A is Benign according to our data. Variant chr7-42040166-G-A is described in ClinVar as Benign. ClinVar VariationId is 255451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.809 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 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.900C>T	p.Ser300Ser	synonymous	Exon 7 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.900C>T	p.Ser300Ser	synonymous	Exon 7 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.900C>T	p.Ser300Ser	synonymous	Exon 7 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.900C>T	p.Ser300Ser	synonymous	Exon 7 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.0740 AC: 11249 AN: 152094 Hom.: 536 Cov.: 33

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0557

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0564

GnomAD2 exomes AF: 0.0693 AC: 17414 AN: 251442 AF XY: 0.0704

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.0348

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0989

Gnomad OTH exome AF: 0.0663

GnomAD4 exome AF: 0.0877 AC: 128178 AN: 1461158 Hom.: 6398 Cov.: 32 AF XY: 0.0864 AC XY: 62843 AN XY: 726952

African (AFR) AF: 0.0338 AC: 1130 AN: 33458

American (AMR) AF: 0.0371 AC: 1657 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 1573 AN: 26132

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39696

South Asian (SAS) AF: 0.0277 AC: 2393 AN: 86248

European-Finnish (FIN) AF: 0.120 AC: 6388 AN: 53418

Middle Eastern (MID) AF: 0.0485 AC: 280 AN: 5768

European-Non Finnish (NFE) AF: 0.0992 AC: 110220 AN: 1111354

Other (OTH) AF: 0.0750 AC: 4527 AN: 60364

GnomAD4 genome AF: 0.0739 AC: 11256 AN: 152212 Hom.: 536 Cov.: 33 AF XY: 0.0731 AC XY: 5444 AN XY: 74428

African (AFR) AF: 0.0349 AC: 1448 AN: 41538

American (AMR) AF: 0.0578 AC: 884 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0557 AC: 193 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4826

European-Finnish (FIN) AF: 0.117 AC: 1240 AN: 10600

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.105 AC: 7124 AN: 67996

Other (OTH) AF: 0.0577 AC: 122 AN: 2116

Alfa AF: 0.0917 Hom.: 407

Bravo AF: 0.0642

Asia WGS AF: 0.0220 AC: 79 AN: 3478

EpiCase AF: 0.0913

EpiControl AF: 0.0861

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	-	1	not provided (1)
-	-	1	Pallister-Hall syndrome (1)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome (1)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome;C1868111:Polysyndactyly 4;C4282400:Polydactyly, postaxial, type A1 (1)
-	-	1	Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.3
DANN	Benign	0.75
PhyloP100		-0.81
Mutation Taster		=71/29	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35961850; hg19: chr7-42079765; COSMIC: COSV67885640;