12-56954960-C-G

Variant names:

• chr12-56954960-C-G
• rs756909031
• NM_003708.5:c.518G>C

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.518G>C​(p.Gly173Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G173D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH16 NM_003708.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• 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, 0.843

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.518G>C	p.Gly173Ala	missense	Exon 2 of 4	NP_003699.3
	RDH16	NM_001320108.2		c.138-1970G>C		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.518G>C	p.Gly173Ala	missense	Exon 2 of 4	ENSP00000381206.3	O75452
	RDH16	ENST00000360752.4	TSL:1	n.2226-1970G>C		intron	N/A
	RDH16	ENST00000869325.1		c.650G>C	p.Gly217Ala	missense	Exon 3 of 5	ENSP00000539384.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.025
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.98	L
PhyloP100		7.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.58
Sift	Benign	0.031	D
Sift4G	Uncertain	0.018	D
Polyphen		0.18	B
Vest4		0.72
MutPred		0.60		Gain of MoRF binding (P = 0.1101)
MVP		0.63
MPC		0.27
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.45
gMVP		0.67
Mutation Taster		=70/30	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: rs756909031; hg19: chr12-57348744;