rs12721454

Variant names:

• chr7-80211023-C-T
• rs12721454
• NM_002069.6:c.645C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_002069.6(GNAI1):​c.645C>T​(p.Phe215Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,612,860 control chromosomes in the GnomAD database, including 1,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.059 (912 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (817 hom.)
• Consequence: GNAI1 NM_002069.6 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.378
• Publications: 4 publications found

Genes affected

GNAI1 (HGNC:4384): (G protein subunit alpha i1) Guanine nucleotide binding proteins are heterotrimeric signal-transducing molecules consisting of alpha, beta, and gamma subunits. The alpha subunit binds guanine nucleotide, can hydrolyze GTP, and can interact with other proteins. The protein encoded by this gene represents the alpha subunit of an inhibitory complex. The encoded protein is part of a complex that responds to beta-adrenergic signals by inhibiting adenylate cyclase. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

GNAI1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 7-80211023-C-T is Benign according to our data. Variant chr7-80211023-C-T is described in ClinVar as [Benign]. Clinvar id is 3056616.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.378 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAI1	NM_002069.6	c.645C>T	p.Phe215Phe	synonymous_variant	Exon 6 of 8	ENST00000649796.2	NP_002060.4
GNAI1	NM_001256414.2	c.489C>T	p.Phe163Phe	synonymous_variant	Exon 6 of 8		NP_001243343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAI1	ENST00000649796.2	c.645C>T	p.Phe215Phe	synonymous_variant	Exon 6 of 8		NM_002069.6	ENSP00000497260.1

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8901 AN: 152064 Hom.: 909 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0154 AC: 3882 AN: 251294 AF XY: 0.0119

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00593 AC: 8662 AN: 1460678 Hom.: 817 Cov.: 29 AF XY: 0.00513 AC XY: 3729 AN XY: 726756

African (AFR) AF: 0.213 AC: 7109 AN: 33406

American (AMR) AF: 0.0115 AC: 514 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5766

European-Non Finnish (NFE) AF: 0.000182 AC: 202 AN: 1110966

Other (OTH) AF: 0.0127 AC: 767 AN: 60350

GnomAD4 genome AF: 0.0586 AC: 8915 AN: 152182 Hom.: 912 Cov.: 32 AF XY: 0.0570 AC XY: 4243 AN XY: 74408

African (AFR) AF: 0.205 AC: 8488 AN: 41486

American (AMR) AF: 0.0202 AC: 309 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68024

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0276 Hom.: 269

Bravo AF: 0.0676

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GNAI1-related disorder Benign:1

Dec 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	7.8
DANN	Benign	0.69
PhyloP100		-0.38
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12721454; hg19: chr7-79840339;