19-48813212-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 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

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

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B14	NM_016246.3	c.776G>A	p.Arg259Gln	missense_variant	Exon 9 of 9	ENST00000263278.9	NP_057330.2
HSD17B14	XM_005258969.5	c.*40G>A		3_prime_UTR_variant	Exon 8 of 8		XP_005259026.1
HSD17B14	XM_047438897.1	c.*368G>A		downstream_gene_variant			XP_047294853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B14	ENST00000263278.9	c.776G>A	p.Arg259Gln	missense_variant	Exon 9 of 9	1	NM_016246.3	ENSP00000263278.3
HSD17B14	ENST00000599157.5	c.704G>A	p.Arg235Gln	missense_variant	Exon 8 of 8	3		ENSP00000472746.1
HSD17B14	ENST00000595764	c.*40G>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000469557.1
HSD17B14	ENST00000596349	c.*40G>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000471631.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000821 AC: 2 AN: 243596 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132410

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776G>A (p.R259Q) alteration is located in exon 9 (coding exon 9) of the HSD17B14 gene. This alteration results from a G to A substitution at nucleotide position 776, causing the arginine (R) at amino acid position 259 to be replaced by a glutamine (Q). 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	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;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.61	N;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.18	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.45	T;.
Sift4G	Benign	0.44	T;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

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: rs141811939; hg19: chr19-49316469;