chr19-10021323-T-C

Position:

• chr19-10021323-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015725.4(RDH8):​c.605T>C​(p.Met202Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 1,613,596 control chromosomes in the GnomAD database, including 196,388 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.52 (21383 hom., cov: 30)
  • Exomes 𝑓: 0.48 (175005 hom.)
• Consequence: RDH8 NM_015725.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.461

Genes affected

RDH8 (HGNC:14423): (retinol dehydrogenase 8) This gene encodes a member of the short-chain dehydrogenase/reductase family. The encoded protein catalyzes the reduction of all-trans-retinal to all-trans-retinol, the first reaction step of the rhodopsin regeneration pathway. This enzymatic reaction is the rate-limiting step in the visual cycle. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.462228E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH8	NM_015725.4	c.605T>C	p.Met202Thr	missense_variant	5/6	ENST00000591589.3	NP_056540.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH8	ENST00000591589.3	c.605T>C	p.Met202Thr	missense_variant	5/6	1	NM_015725.4	ENSP00000466058.2
RDH8	ENST00000651512.1	c.665T>C	p.Met222Thr	missense_variant	5/6			ENSP00000498711.1
RDH8	ENST00000587782.1	c.49T>C	p.Trp17Arg	missense_variant	2/3	2		ENSP00000465773.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79587 AN: 151658 Hom.: 21352 Cov.: 30

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.524 AC: 131845 AN: 251406 Hom.: 35616 AF XY: 0.527 AC XY: 71558 AN XY: 135886

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.490

Gnomad EAS exome AF: 0.552

Gnomad SAS exome AF: 0.672

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.484 AC: 708170 AN: 1461818 Hom.: 175005 Cov.: 55 AF XY: 0.489 AC XY: 355428 AN XY: 727224

Gnomad4 AFR exome AF: 0.628

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.665

Gnomad4 FIN exome AF: 0.523

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.525 AC: 79680 AN: 151778 Hom.: 21383 Cov.: 30 AF XY: 0.531 AC XY: 39404 AN XY: 74178

Gnomad4 AFR AF: 0.618

Gnomad4 AMR AF: 0.552

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.550

Gnomad4 SAS AF: 0.677

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.528

Alfa AF: 0.471 Hom.: 41499

Bravo AF: 0.526

TwinsUK AF: 0.460 AC: 1706

ALSPAC AF: 0.471 AC: 1817

ESP6500AA AF: 0.616 AC: 2715

ESP6500EA AF: 0.454 AC: 3907

ExAC AF: 0.520 AC: 63135

Asia WGS AF: 0.637 AC: 2217 AN: 3478

EpiCase AF: 0.463

EpiControl AF: 0.458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.17
DANN	Benign	0.39
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.048	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.56	T
Vest4		0.0060
MPC		0.17
ClinPred		0.0044	T
GERP RS		-2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1644731; hg19: chr19-10131999; COSMIC: COSV50675294; COSMIC: COSV50675294;