4-109837475-A-G

Position:

• chr4-109837475-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006583.5(RRH):​c.590A>G​(p.Asn197Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RRH NM_006583.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.84

Genes affected

RRH (HGNC:10450): (retinal pigment epithelium-derived rhodopsin homolog) Opsins are members of the guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. This gene belongs to the seven-exon subfamily of mammalian opsin genes that includes opsin 5 and retinal G protein coupled receptor. [provided by RefSeq, Jul 2008]

RRH (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRH	NM_006583.5	c.590A>G	p.Asn197Ser	missense_variant	5/7	ENST00000317735.7	NP_006574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRH	ENST00000317735.7	c.590A>G	p.Asn197Ser	missense_variant	5/7	1	NM_006583.5	ENSP00000314992.4
RRH	ENST00000652276.1	c.443+1315A>G		intron_variant				ENSP00000498977.1
RRH	ENST00000650907.1	n.1648A>G		non_coding_transcript_exon_variant	4/6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.590A>G (p.N197S) alteration is located in exon 5 (coding exon 5) of the RRH gene. This alteration results from a A to G substitution at nucleotide position 590, causing the asparagine (N) at amino acid position 197 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.030	N
REVEL	Uncertain	0.35
Sift	Benign	0.55	T
Sift4G	Benign	0.49	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.51		Gain of glycosylation at N197 (P = 0.0774);
MVP		0.95
MPC		0.17
ClinPred		0.91	D
GERP RS		5.9
Varity_R		0.30
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-110758631;