chr19-48813212-C-T

Variant names:

• chr19-48813212-C-T
• rs141811939
• NM_016246.3:c.776G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016246.3(HSD17B14):​c.776G>A​(p.Arg259Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,456,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HSD17B14 NM_016246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.17
• Publications: 0 publications found

Genes affected

HSD17B14 (HGNC:23238): (hydroxysteroid 17-beta dehydrogenase 14) 17-beta-hydroxysteroid dehydrogenases, such as HSD17B14, are primarily involved in metabolism of steroids at the C17 position and also of other substrates, such as fatty acids, prostaglandins, and xenobiotics (Lukacik et al., 2007 [PubMed 17067289]).[supplied by OMIM, Jun 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04177174).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016246.3. 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
	HSD17B14	NM_016246.3	MANE Select	c.776G>A	p.Arg259Gln	missense	Exon 9 of 9	NP_057330.2	Q9BPX1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B14	ENST00000263278.9	TSL:1 MANE Select	c.776G>A	p.Arg259Gln	missense	Exon 9 of 9	ENSP00000263278.3	Q9BPX1
	HSD17B14	ENST00000867480.1		c.902G>A	p.Arg301Gln	missense	Exon 10 of 10	ENSP00000537539.1
	HSD17B14	ENST00000867481.1		c.785G>A	p.Arg262Gln	missense	Exon 9 of 9	ENSP00000537540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000821 AC: 2 AN: 243596 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1456612 Hom.: 0 Cov.: 32 AF XY: 0.00000690 AC XY: 5 AN XY: 724166

African (AFR) AF: 0.0000300 AC: 1 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5016

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109646

Other (OTH) AF: 0.0000166 AC: 1 AN: 60122

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.029
DANN	Benign	0.91
DEOGEN2	Benign	0.00086	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.61	N
PhyloP100		-3.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.18	N
REVEL	Uncertain	0.30
Sift	Benign	0.45	T
Sift4G	Benign	0.44	T
Polyphen		0.0050	B
Vest4		0.086
MutPred		0.35		Loss of sheet (P = 0.0457)
MVP		0.19
MPC		0.29
ClinPred		0.037	T
GERP RS		-8.8
Varity_R		0.060
gMVP		0.33
Mutation Taster		=96/4	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: rs141811939; hg19: chr19-49316469; COSMIC: COSV107207635; COSMIC: COSV107207635;