rs141521563

Positions:

chr2-233320749-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000541.5(SAG):c.301G>A(p.Ala101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,605,992 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0049 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 33 hom. )

Consequence

SAG
NM_000541.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.611

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00363034).

BP6

Variant 2-233320749-G-A is Benign according to our data. Variant chr2-233320749-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167633.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr2-233320749-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00495 (753/152244) while in subpopulation AMR AF= 0.0103 (157/15300). AF 95% confidence interval is 0.00895. There are 5 homozygotes in gnomad4. There are 350 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAG	NM_000541.5 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	5/16	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.301G>A	p.Ala101Thr	missense_variant	5/16	5	NM_000541.5	ENSP00000386444.1		P10523

Frequencies

GnomAD3 genomes

AF:

0.00494

AC:

751

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00697

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00465

AC:

1088

AN:

234002

Hom.:

AF XY:

0.00479

AC XY:

608

AN XY:

126878

show subpopulations

Gnomad AFR exome

AF:

0.000789

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.00524

Gnomad EAS exome

AF:

0.000176

Gnomad SAS exome

AF:

0.00370

Gnomad FIN exome

AF:

0.000290

Gnomad NFE exome

AF:

0.00631

Gnomad OTH exome

AF:

0.00974

GnomAD4 exome

AF:

0.00550

AC:

7989

AN:

1453748

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

4015

AN XY:

722358

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.00652

Gnomad4 ASJ exome

AF:

0.00385

Gnomad4 EAS exome

AF:

0.0000762

Gnomad4 SAS exome

AF:

0.00394

Gnomad4 FIN exome

AF:

0.000796

Gnomad4 NFE exome

AF:

0.00604

Gnomad4 OTH exome

AF:

0.00602

GnomAD4 genome

AF:

0.00495

AC:

753

AN:

152244

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

350

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00697

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00626

Hom.:

Bravo

AF:

0.00605

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00181

AC:

ESP6500EA

AF:

0.00700

AC:

ExAC

AF:

0.00452

AC:

546

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Oguchi disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Retinal dystrophy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.039

.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.041

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.27

.;N

PrimateAI

Benign

0.23

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.082

Sift

Benign

0.39

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.016

.;B

Vest4

0.085

MVP

0.25

MPC

0.12

ClinPred

0.0046

GERP RS

-0.75

Varity_R

0.049

gMVP

0.18

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