4-109836013-G-A

Position:

• chr4-109836013-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006583.5(RRH):​c.404G>A​(p.Arg135Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RRH NM_006583.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14893833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRH	NM_006583.5	c.404G>A	p.Arg135Lys	missense_variant	4/7	ENST00000317735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRH	ENST00000317735.7	c.404G>A	p.Arg135Lys	missense_variant	4/7	1	NM_006583.5	P1
RRH	ENST00000652276.1	c.299G>A	p.Arg100Lys	missense_variant	3/4
RRH	ENST00000650907.1	n.1462G>A		non_coding_transcript_exon_variant	3/6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 04, 2024

The c.404G>A (p.R135K) alteration is located in exon 4 (coding exon 4) of the RRH gene. This alteration results from a G to A substitution at nucleotide position 404, causing the arginine (R) at amino acid position 135 to be replaced by a lysine (K). 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	0.091
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.42
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.23	N
MutationTaster	Benign	0.96	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.073
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.65		Gain of ubiquitination at R135 (P = 0.0337);
MVP		0.45
MPC		0.025
ClinPred		0.51	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.61

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-110757169;