2-233309256-GACAAATCGGTGAGTGGTGC-G
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000541.5(SAG):c.72_75+15del variant causes a splice donor, splice donor 5th base, coding sequence, intron change. The variant allele was found at a frequency of 0.00000434 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SAG
NM_000541.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
NM_000541.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.10
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.1, offset of -4, new splice context is: caaGTgagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP5
Variant 2-233309256-GACAAATCGGTGAGTGGTGC-G is Pathogenic according to our data. Variant chr2-233309256-GACAAATCGGTGAGTGGTGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1511520.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-233309256-GACAAATCGGTGAGTGGTGC-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SAG | NM_000541.5 | c.72_75+15del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 2/16 | ENST00000409110.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SAG | ENST00000409110.6 | c.72_75+15del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 2/16 | 5 | NM_000541.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 248946Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135060
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461106Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726854
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74482
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2022 | This variant results in the deletion of part of exon 2 (c.72_75+15del) of the SAG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SAG are known to be pathogenic (PMID: 9452120, 15234147, 22665972). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1511520). This variant is also known as c.68_75+11del. This variant has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 30245926, 31054281). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at