rs374913800

Positions:

chr3-50194806-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_144499.3(GNAT1):c.904C>T(p.Gln302Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

GNAT1
NM_144499.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.56

Variant links:

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]

GNAT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 3-50194806-C-T is Pathogenic according to our data. Variant chr3-50194806-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-50194806-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-50194806-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAT1	NM_144499.3 linkuse as main transcript	c.904C>T	p.Gln302Ter	stop_gained	8/9	ENST00000232461.8
GNAT1	NM_000172.4 linkuse as main transcript	c.904C>T	p.Gln302Ter	stop_gained	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAT1	ENST00000232461.8 linkuse as main transcript	c.904C>T	p.Gln302Ter	stop_gained	8/9	5	NM_144499.3	P1
GNAT1	ENST00000433068.5 linkuse as main transcript	c.904C>T	p.Gln302Ter	stop_gained	8/9	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251078

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000739

AC:

108

AN:

1461634

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000944

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000718

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital stationary night blindness 1G

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 22, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 07, 2018	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 49 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 31589614, 26472407, 27624628, 27977773, 29850563, 26822852, 31736247) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2023	This sequence change creates a premature translational stop signal (p.Gln302*) in the GNAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNAT1 are known to be pathogenic (PMID: 11095744, 31736247). This variant is present in population databases (rs374913800, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with autosomal recessive retinal dystrophy (PMID: 26472407, 27624628). This variant has been reported in individual(s) with autosomal dominant night blindness (Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 488669). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Benign

0.65

MutationTaster

Benign

1.0

A;A

Vest4

0.92

GERP RS

4.9

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over