4-87310294-T-C

Variant names:

• chr4-87310294-T-C
• rs1734503504
• NM_178135.5:c.761A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178135.5(HSD17B13):​c.761A>G​(p.Lys254Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD17B13 NM_178135.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35
• Publications: 0 publications found

Genes affected

HSD17B13 (HGNC:18685): (hydroxysteroid 17-beta dehydrogenase 13) Predicted to enable oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor and steroid dehydrogenase activity. Acts upstream of or within positive regulation of lipid biosynthetic process. Located in lipid droplet. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2758411).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B13	NM_178135.5	c.761A>G	p.Lys254Arg	missense_variant	Exon 6 of 7	ENST00000328546.5	NP_835236.2
HSD17B13	NM_001136230.3	c.653A>G	p.Lys218Arg	missense_variant	Exon 5 of 6		NP_001129702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B13	ENST00000328546.5	c.761A>G	p.Lys254Arg	missense_variant	Exon 6 of 7	1	NM_178135.5	ENSP00000333300.4
HSD17B13	ENST00000302219.10	c.653A>G	p.Lys218Arg	missense_variant	Exon 5 of 6	1		ENSP00000305438.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.761A>G (p.K254R) alteration is located in exon 6 (coding exon 6) of the HSD17B13 gene. This alteration results from a A to G substitution at nucleotide position 761, causing the lysine (K) at amino acid position 254 to be replaced by an arginine (R). 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	0.082
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0044	.;T
Eigen	Benign	0.046
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.6	.;M
PhyloP100		3.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.030	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.75	P;B
Vest4		0.41
MutPred		0.46		.;Loss of methylation at K254 (P = 0.0265);
MVP		0.88
MPC		0.092
ClinPred		0.70	D
GERP RS		3.9
Varity_R		0.090
gMVP		0.27
Mutation Taster		=95/5	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: rs1734503504; hg19: chr4-88231446;