7-80189098-A-C

Position:

• chr7-80189098-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002069.6(GNAI1):​c.170A>C​(p.His57Pro) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAI1 NM_002069.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAI1	NM_002069.6	c.170A>C	p.His57Pro	missense_variant	3/8	ENST00000649796.2	NP_002060.4
GNAI1	NM_001256414.2	c.14A>C	p.His5Pro	missense_variant	3/8		NP_001243343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAI1	ENST00000649796.2	c.170A>C	p.His57Pro	missense_variant	3/8		NM_002069.6	ENSP00000497260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant classified as Uncertain significance and reported on 06-16-2022 by The Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.1	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Uncertain	0.0070	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Vest4		0.95, 0.94
MutPred		0.87		Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);Gain of catalytic residue at H57 (P = 0.0116);.;
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.98

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: chr7-79818414;