rs1000548

Variant names:

• chr2-233326656-T-C
• rs1000548
• NM_000541.5:c.436-465T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000541.5(SAG):​c.436-465T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 151,706 control chromosomes in the GnomAD database, including 416 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.067 (416 hom., cov: 31)
• Consequence: SAG NM_000541.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAG	NM_000541.5	c.436-465T>C		intron_variant	Intron 6 of 15	ENST00000409110.6	NP_000532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAG	ENST00000409110.6	c.436-465T>C		intron_variant	Intron 6 of 15	5	NM_000541.5	ENSP00000386444.1

Frequencies

GnomAD3 genomes AF: 0.0671 AC: 10177 AN: 151654 Hom.: 416 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0612

Gnomad EAS AF: 0.0228

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0835

Gnomad MID AF: 0.0321

Gnomad NFE AF: 0.0508

Gnomad OTH AF: 0.0639

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0671 AC: 10186 AN: 151706 Hom.: 416 Cov.: 31 AF XY: 0.0682 AC XY: 5052 AN XY: 74062

African (AFR) AF: 0.101 AC: 4176 AN: 41306

American (AMR) AF: 0.0439 AC: 671 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0612 AC: 212 AN: 3466

East Asian (EAS) AF: 0.0231 AC: 119 AN: 5158

South Asian (SAS) AF: 0.104 AC: 499 AN: 4792

European-Finnish (FIN) AF: 0.0835 AC: 872 AN: 10438

Middle Eastern (MID) AF: 0.0280 AC: 8 AN: 286

European-Non Finnish (NFE) AF: 0.0508 AC: 3454 AN: 67980

Other (OTH) AF: 0.0672 AC: 141 AN: 2098

Alfa AF: 0.0576 Hom.: 66

Bravo AF: 0.0645

Asia WGS AF: 0.0880 AC: 306 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.23
DANN	Benign	0.70
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1000548; hg19: chr2-234235302;