7-80188987-A-C

Position:

• chr7-80188987-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM2 PP3_Strong PP5_Moderate

The NM_002069.6(GNAI1):​c.155A>C​(p.Gln52Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAI1 NM_002069.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.50

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 10 ACMG points.

• PS1: Transcript NM_002069.6 (GNAI1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 7-80188987-A-C is Pathogenic according to our data. Variant chr7-80188987-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 987048.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-80188987-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAI1	NM_002069.6	c.155A>C	p.Gln52Pro	missense_variant	2/8	ENST00000649796.2	NP_002060.4
GNAI1	NM_001256414.2	c.-2A>C		5_prime_UTR_variant	2/8		NP_001243343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAI1	ENST00000649796.2	c.155A>C	p.Gln52Pro	missense_variant	2/8		NM_002069.6	ENSP00000497260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
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	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.8	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0010	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Vest4		0.89
MutPred		0.91		Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.95
gMVP		1.0

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: rs1788434582; hg19: chr7-79818303;