1-109548825-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006496.4(GNAI3):c.105G>A(p.Lys35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,532,620 control chromosomes in the GnomAD database, including 856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (59 hom., cov: 32)
  • Exomes 𝑓: 0.032 (797 hom.)
• Consequence: GNAI3 NM_006496.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.19

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-109548825-G-A is Benign according to our data. Variant chr1-109548825-G-A is described in ClinVar as [Benign]. Clinvar id is 1243082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0234 (3563/152322) while in subpopulation NFE AF= 0.033 (2245/68012). AF 95% confidence interval is 0.0319. There are 59 homozygotes in gnomad4. There are 1767 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3564 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAI3	NM_006496.4	c.105G>A	p.Lys35=	synonymous_variant	1/9	ENST00000369851.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI3	ENST00000369851.7	c.105G>A	p.Lys35=	synonymous_variant	1/9	1	NM_006496.4	P1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3564 AN: 152204 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00535

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0251 AC: 6094 AN: 242420 Hom.: 127 AF XY: 0.0249 AC XY: 3260 AN XY: 131022

Gnomad AFR exome AF: 0.00556

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.00740

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0318 AC: 43846 AN: 1380298 Hom.: 797 Cov.: 27 AF XY: 0.0310 AC XY: 21349 AN XY: 689654

Gnomad4 AFR exome AF: 0.00589

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.0000765

Gnomad4 SAS exome AF: 0.00724

Gnomad4 FIN exome AF: 0.0554

Gnomad4 NFE exome AF: 0.0355

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0234 AC: 3563 AN: 152322 Hom.: 59 Cov.: 32 AF XY: 0.0237 AC XY: 1767 AN XY: 74480

Gnomad4 AFR AF: 0.00534

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0527

Gnomad4 NFE AF: 0.0330

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0281 Hom.: 41

Bravo AF: 0.0203

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	13
Dann	Benign	0.94
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230350; hg19: chr1-110091447; COSMIC: COSV63983438; COSMIC: COSV63983438;