dbSNP rs387907178: GNAI3:p.Gly40Ser (chr1-109548838-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_006496.4(GNAI3):c.118G>A(p.Gly40Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G40V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAI3
NM_006496.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.72

Publications

10 publications found

Variant links:

Genes affected

GNAI3 (HGNC:4387): (G protein subunit alpha i3) Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling pathways. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes an alpha subunit and belongs to the G-alpha family. Mutation in this gene, resulting in a gly40-to-arg substitution, is associated with auriculocondylar syndrome, and shown to affect downstream targets in the G protein-coupled endothelin receptor pathway. [provided by RefSeq, Jun 2012]

GNAI3 Gene-Disease associations (from GenCC):

auriculocondylar syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
auriculocondylar syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GNAI3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006496.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-109573737-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1809757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAI3	NM_006496.4 link	c.118G>A	p.Gly40Ser	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000369851.7	NP_006487.1	P08754

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAI3	ENST00000369851.7 link	c.118G>A	p.Gly40Ser	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_006496.4	ENSP00000358867.4		P08754

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

240118

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1430720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712962

African (AFR)

AF:

0.00

AC:

AN:

32920

American (AMR)

AF:

0.00

AC:

AN:

43988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25788

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.00

AC:

AN:

84718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085712

Other (OTH)

AF:

0.00

AC:

AN:

59346

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

PhyloP100

9.7

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.92

MutPred

0.93

Gain of phosphorylation at G40 (P = 0.0786);

MVP

0.99

MPC

1.5

ClinPred

1.0

GERP RS

5.8

PromoterAI

-0.17

Neutral

(source)

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

3.5

Varity_R

0.92

gMVP

0.94

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over