1-109548838-G-C

Position:

• chr1-109548838-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_006496.4(GNAI3):​c.118G>C​(p.Gly40Arg) 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. 15/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAI3 NM_006496.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.72

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 1-109548838-G-C is Pathogenic according to our data. Variant chr1-109548838-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-109548838-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAI3	NM_006496.4	c.118G>C	p.Gly40Arg	missense_variant, splice_region_variant	1/9	ENST00000369851.7	NP_006487.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAI3	ENST00000369851.7	c.118G>C	p.Gly40Arg	missense_variant, splice_region_variant	1/9	1	NM_006496.4	ENSP00000358867	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Auriculocondylar syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	University of Washington Center for Mendelian Genomics, University of Washington	Sep 17, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 04, 2012	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 18, 2023

In silico analyses support that this missense variant has a deleterious effect on protein structure/function and may impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22560091) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.87		Gain of MoRF binding (P = 0.0045);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		3.5
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: -19

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907178; hg19: chr1-110091460;