NM_144499.3:c.113G>A

Variant names:

• chr3-50193139-G-A
• rs104893740
• NM_144499.3:c.113G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_144499.3(GNAT1):​c.113G>A​(p.Gly38Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,700 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNAT1 NM_144499.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.59
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• congenital stationary night blindness autosomal dominant 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• inherited retinal dystrophy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal degeneration

  Inheritance: AR Classification: STRONG Submitted by: G2P
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital stationary night blindness 1G

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_144499.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 3-50193139-G-A is Pathogenic according to our data. Variant chr3-50193139-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15926.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144499.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAT1	NM_144499.3	MANE Select	c.113G>A	p.Gly38Asp	missense	Exon 2 of 9	NP_653082.1	P11488
	GNAT1	NM_000172.4		c.113G>A	p.Gly38Asp	missense	Exon 2 of 9	NP_000163.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAT1	ENST00000232461.8	TSL:5 MANE Select	c.113G>A	p.Gly38Asp	missense	Exon 2 of 9	ENSP00000232461.3	P11488
	GNAT1	ENST00000440836.1	TSL:3	c.-32G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000403537.1	C9JCV8
	GNAT1	ENST00000433068.5	TSL:5	c.113G>A	p.Gly38Asp	missense	Exon 2 of 9	ENSP00000387555.1	P11488

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251172 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital stationary night blindness autosomal dominant 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.95		Loss of catalytic residue at G38 (P = 0.0399)
MVP		0.92
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.0056	Neutral
Varity_R		0.95
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs104893740; hg19: chr3-50230572;