chr3-50191783-A-G

Position:

• chr3-50191783-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144499.3(GNAT1):​c.58A>G​(p.Lys20Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNAT1 NM_144499.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

Genes affected

GNAT1 (HGNC:4393): (G protein subunit alpha transducin 1) Transducin is a 3-subunit guanine nucleotide-binding protein (G protein) which stimulates the coupling of rhodopsin and cGMP-phoshodiesterase during visual impulses. The transducin alpha subunits in rods and cones are encoded by separate genes. This gene encodes the alpha subunit in rods. This gene is also expressed in other cells, and has been implicated in bitter taste transduction in rat taste cells. Mutations in this gene result in autosomal dominant congenital stationary night blindness. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32302788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAT1	NM_144499.3	c.58A>G	p.Lys20Glu	missense_variant	1/9	ENST00000232461.8	NP_653082.1
GNAT1	NM_000172.4	c.58A>G	p.Lys20Glu	missense_variant	1/9		NP_000163.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAT1	ENST00000232461.8	c.58A>G	p.Lys20Glu	missense_variant	1/9	5	NM_144499.3	ENSP00000232461.3
GNAT1	ENST00000433068.5	c.58A>G	p.Lys20Glu	missense_variant	1/9	5		ENSP00000387555.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461748 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2022

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 20 of the GNAT1 protein (p.Lys20Glu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with GNAT1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.44	T;T
Polyphen		0.0060	B;B
Vest4		0.40
MutPred		0.50		Loss of MoRF binding (P = 0.0146);Loss of MoRF binding (P = 0.0146);
MVP		0.92
MPC		0.96
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.84
gMVP		0.58

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: rs1699414848; hg19: chr3-50229216;