chr2-233335078-CA-C

Position:

chr2-233335078-CA-C

Variant summary

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

The NM_000541.5(SAG):c.926delA(p.Asn309fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,840 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

SAG
NM_000541.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -1.84

Variant links:

Genes affected

SAG (HGNC:10521): (S-antigen visual arrestin) Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. S-arrestin, also known as S-antigen, is a major soluble photoreceptor protein that is involved in desensitization of the photoactivated transduction cascade. It is expressed in the retina and the pineal gland and inhibits coupling of rhodopsin to transducin in vitro. Additionally, S-arrestin is highly antigenic, and is capable of inducing experimental autoimmune uveoretinitis. Mutations in this gene have been associated with Oguchi disease, a rare autosomal recessive form of night blindness. [provided by RefSeq, Jul 2008]

SAG links:

SAG (HGNC:):

SAG 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 2-233335078-CA-C is Pathogenic according to our data. Variant chr2-233335078-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 12951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233335078-CA-C is described in Lovd as [Pathogenic]. Variant chr2-233335078-CA-C is described in Lovd as [Pathogenic]. Variant chr2-233335078-CA-C is described in Lovd as [Likely_pathogenic]. Variant chr2-233335078-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAG	NM_000541.5 linkuse as main transcript	c.926delA	p.Asn309fs	frameshift_variant	11/16	ENST00000409110.6	NP_000532.2	P10523

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAG	ENST00000409110.6 linkuse as main transcript	c.926delA	p.Asn309fs	frameshift_variant	11/16	5	NM_000541.5	ENSP00000386444.1		P10523

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152260

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:

0.000962

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248846

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135010

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS 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:

0.0000376

AC:

AN:

1461462

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00139

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

AF:

0.0000328

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oguchi disease

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	The c.926delA (p.Asn309Thrfs12) frameshift variant in the SAG gene is a known variant that is predicted to introduce a premature termination codon. It has been previously reported in at least eight individuals affected with autosomal recessive Oguchi Disease (Fuchs et al., 1995; Nakamura et al., 2004; Hayashi et al., 2011; Katagiri et al., 2014). In one of the affected individuals, this variant was reported in trans with a likely pathogenic nonsense variant (Arg175ter) (Nakamura et al., 2004). Frameshift and nonsense variants are the only types of variants reported in affected individuals; this suggests that loss-of-function is a common mechanism of disease. This variant is absent or present at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; ExAC = 0.035%). Therefore, this collective evidence supports the classification of the c.926delA (p.Asn309Thrfs12) as a Pathogenic variant for Oguchi Disease. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2004	- -

SAG-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 09, 2017

Across a selection of the available literature, the SAG c.926delA (p.Asn309ThrfsTer12) variant has been identified in a homozygous state in 18 patients and in a heterozygous state in one patient, all of whom were diagnosed with Oguchi disease or retinitis pigmentosa (Fuchs et al. 1995; Saga et al. 2004; Yoshida et al. 2006; Fujinami et al. 2011; Hayashi et al. 2011; Sonoyama et al. 2011; Katagiri et al. 2014). The variant was also found in at least 12 unaffected heterozygous carriers (Fuchs et al. 1994; Yoshida et al. 2006). The p.Asn309ThrfsTer12 variant was reported in six of 1368 control alleles and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. The p.Asn309ThrfsTer12 variant is reported to be the most common cause of Oguchi disease in Japanese individuals where it has been shown to be inherited from a single founder (Saga et al. 2004). Based on the collective evidence, the p.Asn309ThrfsTer12 variant is classified as pathogenic for SAG-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinitis pigmentosa 47

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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