rs201070431

Variant names:

• chr7-42026234-C-T
• rs201070431
• NM_000168.6:c.1207G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-42026234-C-T
• chr7-42026234-C-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000168.6(GLI3):​c.1207G>A​(p.Val403Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.19
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08550164).
• BP6: Variant 7-42026234-C-T is Benign according to our data. Variant chr7-42026234-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211081.

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.1207G>A	p.Val403Ile	missense	Exon 8 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.1207G>A	p.Val403Ile	missense	Exon 8 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.1207G>A	p.Val403Ile	missense	Exon 8 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.1207G>A	p.Val403Ile	missense	Exon 8 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000839 AC: 21 AN: 250226 AF XY: 0.0000666

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1461480 Hom.: 0 Cov.: 32 AF XY: 0.000103 AC XY: 75 AN XY: 726984

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000895 AC: 4 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000139 AC: 155 AN: 1111806

Other (OTH) AF: 0.000199 AC: 12 AN: 60374

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152120 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74322

African (AFR) AF: 0.0000966 AC: 4 AN: 41426

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Pallister-Hall syndrome (1)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome (1)
-	-	1	Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.047
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.24
MPC		0.12
ClinPred		0.034	T
GERP RS		4.0
Varity_R		0.090
gMVP		0.15
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201070431; hg19: chr7-42065833;