NM_000541.5:c.31G>C

Variant names:

• chr2-233309220-G-C
• rs200078242
• NM_000541.5:c.31G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000541.5(SAG):​c.31G>C​(p.Glu11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E11K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SAG NM_000541.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376
• Publications: 0 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):

• Oguchi disease-1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 47

  Inheritance: SD, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07538435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000541.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAG	NM_000541.5	MANE Select	c.31G>C	p.Glu11Gln	missense	Exon 2 of 16	NP_000532.2	P10523

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAG	ENST00000409110.6	TSL:5 MANE Select	c.31G>C	p.Glu11Gln	missense	Exon 2 of 16	ENSP00000386444.1	P10523
	SAG	ENST00000462487.5	TSL:1	n.144+1198G>C		intron	N/A
	SAG	ENST00000447536.5	TSL:3	c.31G>C	p.Glu11Gln	missense	Exon 2 of 7	ENSP00000408937.1	E7ESX4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461492 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727026

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111758

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.15
DANN	Benign	0.52
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.38
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.15
Sift	Benign	0.27	T
Sift4G	Benign	0.43	T
Polyphen		0.046	B
Vest4		0.10
MutPred		0.31		Loss of ubiquitination at K6 (P = 0.02)
MVP		0.39
MPC		0.13
ClinPred		0.17	T
GERP RS		-3.2
Varity_R		0.043
gMVP		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200078242; hg19: chr2-234217866;