chr2-233335078-CA-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000541.5(SAG):c.926delA(p.Asn309ThrfsTer12) 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:6

Conservation

PhyloP100: -1.84

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

retinitis pigmentosa 47
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Oguchi disease-1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 96
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinal disorder
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Oguchi disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SAG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 CliVar 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 CliVar as Pathogenic. Clinvar id is 12951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAG	NM_000541.5 link	c.926delA	p.Asn309ThrfsTer12	frameshift_variant	Exon 11 of 16	ENST00000409110.6	NP_000532.2	P10523

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAG	ENST00000409110.6 link	c.926delA	p.Asn309ThrfsTer12	frameshift_variant	Exon 11 of 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

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248846

AF XY:

0.00000741

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 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

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00139

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111732

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000964

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oguchi disease

Pathogenic:2

Jul 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 30, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.926delA (p.Asn309Thrfs*12) 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.Asn309Thrfs*12) as a Pathogenic variant for Oguchi Disease. -

SAG-related disorder

Pathogenic:1

May 09, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Asn309Thrfs*12) in the SAG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SAG are known to be pathogenic (PMID: 9452120, 15234147, 22665972). This variant is present in population databases (rs754158163, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Oguchi disease or retinitis pigmentosa (PMID: 7670478, 21447990, 21987685, 25268133, 31213501, 31257036). This variant is also known as 1147delA and c.924delA. ClinVar contains an entry for this variant (Variation ID: 12951). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 47

Pathogenic:1

Jul 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinal dystrophy

Pathogenic:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.8

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over