chr7-80188975-C-A

Position:

• chr7-80188975-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_002069.6(GNAI1):​c.143C>A​(p.Thr48Lys) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T48P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAI1 NM_002069.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.89

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 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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 chr7-80188974-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1172689.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 7-80188975-C-A is Pathogenic according to our data. Variant chr7-80188975-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 873455.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAI1	NM_002069.6	c.143C>A	p.Thr48Lys	missense_variant	2/8	ENST00000649796.2
GNAI1	NM_001256414.2	c.-14C>A		5_prime_UTR_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI1	ENST00000649796.2	c.143C>A	p.Thr48Lys	missense_variant	2/8		NM_002069.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455502 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2022

- -

Neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 21, 2019

The variant was identified as de novo (maternity and paternity confirmed) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	0.99
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	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.97	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;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.8	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Vest4		0.89
MutPred		0.84		Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);Gain of methylation at T48 (P = 0.0163);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1788434338; hg19: chr7-79818291;