4-109836032-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS2

The NM_006583.5(RRH):c.423C>A(p.Tyr141Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,614,202 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: RRH NM_006583.5 stop_gained
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.464

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 Likely_benign. Variant got -4 ACMG points.

• PM4: Stoplost variant in NM_006583.5 Downstream stopcodon found after 355 codons.
• BP6: Variant 4-109836032-C-A is Benign according to our data. Variant chr4-109836032-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 738236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRH	NM_006583.5	c.423C>A	p.Tyr141Ter	stop_gained	4/7	ENST00000317735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRH	ENST00000317735.7	c.423C>A	p.Tyr141Ter	stop_gained	4/7	1	NM_006583.5	P1
RRH	ENST00000652276.1	c.318C>A	p.Tyr106Ter	stop_gained	3/4
RRH	ENST00000650907.1	n.1481C>A		non_coding_transcript_exon_variant	3/6

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000374 AC: 94 AN: 251488 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135920

Gnomad AFR exome AF: 0.00547

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 101 AN XY: 727236

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.00165 AC: 252 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74474

Gnomad4 AFR AF: 0.00584

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000316 Hom.: 0

Bravo AF: 0.00168

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000436 AC: 53

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Benign	0.095
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.43	N
MutationTaster	Benign	1.0	A
Vest4		0.97
GERP RS		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs115617845; hg19: chr4-110757188;