Variant chr7-80135278-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_002069.6(GNAI1):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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G40C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GNAI1
NM_002069.6 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.44

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a strand (size 8) in uniprot entity GNAI1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002069.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-80135278-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685334.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 7-80135278-G-C is Pathogenic according to our data. Variant chr7-80135278-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2577995.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAI1	NM_002069.6 linkuse as main transcript	c.118G>C	p.Gly40Arg	missense_variant, splice_region_variant	1/8	ENST00000649796.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI1	ENST00000649796.2 linkuse as main transcript	c.118G>C	p.Gly40Arg	missense_variant, splice_region_variant	1/8		NM_002069.6	P1	P63096-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics laboratory, Necker Hospital

May 25, 2021

- -

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

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-6.3

.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.

Sift4G

Uncertain

0.0030

.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

Vest4

0.95

MutPred

0.91

Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);

MVP

0.98

MPC

2.2

ClinPred

1.0

GERP RS

3.9

Varity_R

0.96

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: -19

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over