NM_000414.4:c.2182A>G

Variant names:

• chr5-119541965-A-G
• rs28943594
• NM_000414.4:c.2182A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000414.4(HSD17B4):​c.2182A>G​(p.Met728Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,612,746 control chromosomes in the GnomAD database, including 401 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (194 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (207 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.51
• Publications: 8 publications found

Genes affected

HSD17B4 (HGNC:5213): (hydroxysteroid 17-beta dehydrogenase 4) The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

HSD17B4 Gene-Disease associations (from GenCC):

• d-bifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000414.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021131337).
• BP6: Variant 5-119541965-A-G is Benign according to our data. Variant chr5-119541965-A-G is described in ClinVar as Benign. ClinVar VariationId is 226670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0939 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000414.4. 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
	HSD17B4	NM_000414.4	MANE Select	c.2182A>G	p.Met728Val	missense	Exon 24 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.2257A>G	p.Met753Val	missense	Exon 25 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.2173A>G	p.Met725Val	missense	Exon 24 of 24	NP_001361426.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.2182A>G	p.Met728Val	missense	Exon 24 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.2113A>G	p.Met705Val	missense	Exon 24 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.2257A>G	p.Met753Val	missense	Exon 25 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4328 AN: 152078 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0197

GnomAD2 exomes AF: 0.00828 AC: 2079 AN: 251230 AF XY: 0.00644

Gnomad AFR exome AF: 0.0972

Gnomad AMR exome AF: 0.00496

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00397 AC: 5798 AN: 1460550 Hom.: 207 Cov.: 30 AF XY: 0.00364 AC XY: 2648 AN XY: 726662

African (AFR) AF: 0.105 AC: 3500 AN: 33336

American (AMR) AF: 0.00509 AC: 227 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00889 AC: 232 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00233 AC: 201 AN: 86234

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53398

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5762

European-Non Finnish (NFE) AF: 0.000973 AC: 1081 AN: 1111106

Other (OTH) AF: 0.00767 AC: 463 AN: 60326

GnomAD4 genome AF: 0.0285 AC: 4342 AN: 152196 Hom.: 194 Cov.: 32 AF XY: 0.0271 AC XY: 2013 AN XY: 74390

African (AFR) AF: 0.0964 AC: 4000 AN: 41508

American (AMR) AF: 0.0104 AC: 159 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68024

Other (OTH) AF: 0.0194 AC: 41 AN: 2108

Alfa AF: 0.0111 Hom.: 150

Bravo AF: 0.0325

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0920 AC: 405

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0102 AC: 1234

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Bifunctional peroxisomal enzyme deficiency (2)
-	-	2	not provided (2)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)
-	-	1	Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.78	N
PhyloP100		3.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.052
Sift	Benign	0.35	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.17
MPC		0.060
ClinPred		0.013	T
GERP RS		3.5
Varity_R		0.077
gMVP		0.38
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28943594; hg19: chr5-118877660;