2-233309263-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BS1_Supporting

The NM_000541.5(SAG):c.74C>T(p.Ser25Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,611,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S25S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SAG NM_000541.5 missense, splice_region
• Scores: Splicing: ADA: 0.9894
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000316 (48/152086) while in subpopulation AMR AF= 0.00223 (34/15276). AF 95% confidence interval is 0.00164. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAG	NM_000541.5	c.74C>T	p.Ser25Leu	missense_variant, splice_region_variant	2/16	ENST00000409110.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAG	ENST00000409110.6	c.74C>T	p.Ser25Leu	missense_variant, splice_region_variant	2/16	5	NM_000541.5	P1

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

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: 0.000176

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000197 AC: 49 AN: 248784 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134968

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000696

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: 0.000204

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 264 AN: 1459824 Hom.: 0 Cov.: 29 AF XY: 0.000178 AC XY: 129 AN XY: 726340

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000364 AC XY: 27 AN XY: 74268

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000291

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000265 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 25 of the SAG protein (p.Ser25Leu). This variant is present in population databases (rs374930316, gnomAD 0.07%). This missense change has been observed in individual(s) with blindness (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 972665). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.81	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.098
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.70
MVP		0.43
MPC		0.37
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.29
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.76
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

Other links and lift over

dbSNP: rs374930316; hg19: chr2-234217909; COSMIC: COSV68590604;