19-10018879-C-T

Variant names:

• chr19-10018879-C-T
• rs2233795
• NM_015725.4:c.411C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015725.4(RDH8):​c.411C>T​(p.Ile137Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,612,906 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (56 hom.)
• Consequence: RDH8 NM_015725.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.741
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 19-10018879-C-T is Benign according to our data. Variant chr19-10018879-C-T is described in ClinVar as Benign. ClinVar VariationId is 783822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.741 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0145 (2214/152264) while in subpopulation AFR AF = 0.0504 (2092/41542). AF 95% confidence interval is 0.0486. There are 50 homozygotes in GnomAd4. There are 1058 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015725.4. 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
	RDH8	NM_015725.4	MANE Select	c.411C>T	p.Ile137Ile	synonymous	Exon 3 of 6	NP_056540.3	Q9NYR8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH8	ENST00000591589.3	TSL:1 MANE Select	c.411C>T	p.Ile137Ile	synonymous	Exon 3 of 6	ENSP00000466058.2	Q9NYR8
	RDH8	ENST00000651512.1		c.471C>T	p.Ile157Ile	synonymous	Exon 3 of 6	ENSP00000498711.1	K7ELF7
	RDH8	ENST00000589570.1	TSL:3	n.50+1664C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2206 AN: 152146 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00379 AC: 949 AN: 250502 AF XY: 0.00260

Gnomad AFR exome AF: 0.0515

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00147 AC: 2147 AN: 1460642 Hom.: 56 Cov.: 31 AF XY: 0.00126 AC XY: 912 AN XY: 726542

African (AFR) AF: 0.0515 AC: 1725 AN: 33464

American (AMR) AF: 0.00251 AC: 112 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.0000900 AC: 100 AN: 1111210

Other (OTH) AF: 0.00318 AC: 192 AN: 60336

GnomAD4 genome AF: 0.0145 AC: 2214 AN: 152264 Hom.: 50 Cov.: 32 AF XY: 0.0142 AC XY: 1058 AN XY: 74448

African (AFR) AF: 0.0504 AC: 2092 AN: 41542

American (AMR) AF: 0.00543 AC: 83 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68028

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0118 Hom.: 44

Bravo AF: 0.0167

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	3.1
DANN	Benign	0.77
PhyloP100		-0.74
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2233795; hg19: chr19-10129555; COSMIC: COSV50674991; COSMIC: COSV50674991;