12-56774024-G-C

Variant names:

• chr12-56774024-G-C
• rs983637457
• NM_003725.4:c.172G>C

Variant summary

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

The NM_003725.4(HSD17B6):​c.172G>C​(p.Ala58Pro) 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. A58T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD17B6 NM_003725.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.37
• Publications: 2 publications found

Genes affected

HSD17B6 (HGNC:23316): (hydroxysteroid 17-beta dehydrogenase 6) The protein encoded by this gene has both oxidoreductase and epimerase activities and is involved in androgen catabolism. The oxidoreductase activity can convert 3 alpha-adiol to dihydrotestosterone, while the epimerase activity can convert androsterone to epi-androsterone. Both reactions use NAD+ as the preferred cofactor. This gene is a member of the retinol dehydrogenase family. [provided by RefSeq, Aug 2013]

ENSG00000309589 (HGNC:):

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, 0.919

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003725.4. 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
	HSD17B6	NM_003725.4	MANE Select	c.172G>C	p.Ala58Pro	missense	Exon 2 of 5	NP_003716.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B6	ENST00000322165.1	TSL:1 MANE Select	c.172G>C	p.Ala58Pro	missense	Exon 2 of 5	ENSP00000318631.1	O14756
	HSD17B6	ENST00000859675.1		c.172G>C	p.Ala58Pro	missense	Exon 2 of 6	ENSP00000529734.1
	HSD17B6	ENST00000554150.5	TSL:5	c.172G>C	p.Ala58Pro	missense	Exon 3 of 6	ENSP00000452273.1	O14756

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.77		Loss of MoRF binding (P = 0.1014)
MVP		0.95
MPC		0.61
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.92
Mutation Taster		=59/41	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: rs983637457; hg19: chr12-57167808;