12-56952151-G-C

Position:

• chr12-56952151-G-C

Variant summary

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

The NM_003708.5(RDH16):​c.832C>G​(p.Arg278Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RDH16 NM_003708.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

Genes affected

RDH16 (HGNC:29674): (retinol dehydrogenase 16) Enables NAD-retinol dehydrogenase activity; androstan-3-alpha,17-beta-diol dehydrogenase activity; and androsterone dehydrogenase activity. Involved in steroid metabolic process. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH16	NM_003708.5	c.832C>G	p.Arg278Gly	missense_variant	4/4	ENST00000398138.5	NP_003699.3
RDH16	NM_001320108.2	c.397C>G	p.Arg133Gly	missense_variant	3/3		NP_001307037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH16	ENST00000398138.5	c.832C>G	p.Arg278Gly	missense_variant	4/4	1	NM_003708.5	ENSP00000381206	P1
RDH16	ENST00000360752.4	n.2485C>G		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000629

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

Mar 24, 2023

The c.832C>G (p.R278G) alteration is located in exon 4 (coding exon 4) of the RDH16 gene. This alteration results from a C to G substitution at nucleotide position 832, causing the arginine (R) at amino acid position 278 to be replaced by a glycine (G). 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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.53	P
Vest4		0.62
MutPred		0.63		Loss of methylation at R278 (P = 0.0137);
MVP		0.76
MPC		0.53
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.31
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs780280835; hg19: chr12-57345935;