7-80188966-G-A

Position:

• chr7-80188966-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002069.6(GNAI1):​c.134G>A​(p.Gly45Asp) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). 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. G45C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAI1 NM_002069.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_002069.6 (GNAI1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a binding_site (size 5) in uniprot entity GNAI1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002069.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 7-80188966-G-A is Pathogenic according to our data. Variant chr7-80188966-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2498283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAI1	NM_002069.6	c.134G>A	p.Gly45Asp	missense_variant	2/8	ENST00000649796.2
GNAI1	NM_001256414.2	c.-23G>A		5_prime_UTR_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI1	ENST00000649796.2	c.134G>A	p.Gly45Asp	missense_variant	2/8		NM_002069.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 17, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.96	D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Vest4		0.91
MutPred		0.94		Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-79818282;