NM_000414.4:c.56C>G

Variant names:

• chr5-119452631-C-G
• rs148363262
• NM_000414.4:c.56C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 4P and 10B. PM1 PM2 BP4_Moderate BP6_Very_Strong

The NM_000414.4(HSD17B4):​c.56C>G​(p.Ala19Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A19T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003769
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.40
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000414.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11119276).
• BP6: Variant 5-119452631-C-G is Benign according to our data. Variant chr5-119452631-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 227431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.56C>G	p.Ala19Gly	missense splice_region	Exon 1 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001374497.1		c.56C>G	p.Ala19Gly	missense splice_region	Exon 1 of 24	NP_001361426.1
	HSD17B4	NM_001199292.2		c.56C>G	p.Ala19Gly	missense splice_region	Exon 1 of 23	NP_001186221.1	P51659-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.56C>G	p.Ala19Gly	missense splice_region	Exon 1 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.56C>G	p.Ala19Gly	missense splice_region	Exon 1 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000515320.5	TSL:2	c.56C>G	p.Ala19Gly	missense splice_region	Exon 1 of 23	ENSP00000424613.1	P51659-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249806 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000411 AC: 6 AN: 1461586 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727114

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111942

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.83
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.51	N
PhyloP100		2.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.88	N
REVEL	Benign	0.22
Sift	Benign	0.82	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.58
ClinPred		0.038	T
GERP RS		2.8
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.18
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148363262; hg19: chr5-118788326;