12-56954994-C-A

Variant names:

• chr12-56954994-C-A
• rs769936511
• NM_003708.5:c.484G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003708.5(RDH16):​c.484G>T​(p.Val162Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V162I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RDH16 NM_003708.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003708.5. 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
	RDH16	NM_003708.5	MANE Select	c.484G>T	p.Val162Phe	missense	Exon 2 of 4	NP_003699.3
	RDH16	NM_001320108.2		c.138-2004G>T		intron	N/A	NP_001307037.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH16	ENST00000398138.5	TSL:1 MANE Select	c.484G>T	p.Val162Phe	missense	Exon 2 of 4	ENSP00000381206.3	O75452
	RDH16	ENST00000360752.4	TSL:1	n.2226-2004G>T		intron	N/A
	RDH16	ENST00000869325.1		c.616G>T	p.Val206Phe	missense	Exon 3 of 5	ENSP00000539384.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249398 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.15
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.80
MutPred		0.54		Loss of MoRF binding (P = 0.1)
MVP		0.62
MPC		0.44
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.60
gMVP		0.77
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs769936511; hg19: chr12-57348778;