1-109573737-G-T

Position:

• chr1-109573737-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006496.4(GNAI3):​c.119G>T​(p.Gly40Val) 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. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G40R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAI3 NM_006496.4 missense, splice_region
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.73

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-109548838-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 1-109573737-G-T is Pathogenic according to our data. Variant chr1-109573737-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1809757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAI3	NM_006496.4	c.119G>T	p.Gly40Val	missense_variant, splice_region_variant	2/9	ENST00000369851.7	NP_006487.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAI3	ENST00000369851.7	c.119G>T	p.Gly40Val	missense_variant, splice_region_variant	2/9	1	NM_006496.4	ENSP00000358867	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2020	This variant occurs de novo in an individual tested at Athena Diagnostics with clinical features associated with auriculocondylar syndrome 1 (MIM: 602483) in the GNAI3 gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein. This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 40 of the GNAI3 protein (p.Gly40Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with auriculocondylar syndrome 1 (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1809757). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Gly40 amino acid residue in GNAI3. Other variant(s) that disrupt this residue have been observed in individuals with GNAI3-related conditions (PMID: 22560091; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.95		Loss of disorder (P = 0.0443);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-110116359;