rs3732933

Variant names:

• chr3-185193363-T-C
• rs3732933
• NM_001966.4:c.1035A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001966.4(EHHADH):​c.1035A>G​(p.Glu345Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,614,088 control chromosomes in the GnomAD database, including 5,761 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.069 (447 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5314 hom.)
• Consequence: EHHADH NM_001966.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 15 publications found

Genes affected

EHHADH (HGNC:3247): (enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase) The protein encoded by this gene is a bifunctional enzyme and is one of the four enzymes of the peroxisomal beta-oxidation pathway. The N-terminal region of the encoded protein contains enoyl-CoA hydratase activity while the C-terminal region contains 3-hydroxyacyl-CoA dehydrogenase activity. Defects in this gene are a cause of peroxisomal disorders such as Zellweger syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

EHHADH Gene-Disease associations (from GenCC):

• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi renotubular syndrome 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001966.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHHADH	NM_001966.4	MANE Select	c.1035A>G	p.Glu345Glu	synonymous	Exon 7 of 7	NP_001957.2
	EHHADH	NM_001166415.2		c.747A>G	p.Glu249Glu	synonymous	Exon 7 of 7	NP_001159887.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHHADH	ENST00000231887.8	TSL:1 MANE Select	c.1035A>G	p.Glu345Glu	synonymous	Exon 7 of 7	ENSP00000231887.3
	EHHADH	ENST00000456310.5	TSL:2	c.747A>G	p.Glu249Glu	synonymous	Exon 7 of 7	ENSP00000387746.1

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10487 AN: 152200 Hom.: 448 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0884

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.0702

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0831 AC: 20864 AN: 250966 AF XY: 0.0857

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0643

Gnomad EAS exome AF: 0.0718

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0792

Gnomad OTH exome AF: 0.0768

GnomAD4 exome AF: 0.0832 AC: 121633 AN: 1461770 Hom.: 5314 Cov.: 32 AF XY: 0.0847 AC XY: 61567 AN XY: 727176

African (AFR) AF: 0.0327 AC: 1093 AN: 33476

American (AMR) AF: 0.109 AC: 4871 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 1752 AN: 26132

East Asian (EAS) AF: 0.0779 AC: 3091 AN: 39698

South Asian (SAS) AF: 0.125 AC: 10806 AN: 86228

European-Finnish (FIN) AF: 0.0563 AC: 3005 AN: 53418

Middle Eastern (MID) AF: 0.0718 AC: 414 AN: 5768

European-Non Finnish (NFE) AF: 0.0826 AC: 91806 AN: 1111960

Other (OTH) AF: 0.0794 AC: 4795 AN: 60390

GnomAD4 genome AF: 0.0689 AC: 10491 AN: 152318 Hom.: 447 Cov.: 32 AF XY: 0.0702 AC XY: 5227 AN XY: 74464

African (AFR) AF: 0.0362 AC: 1505 AN: 41570

American (AMR) AF: 0.0888 AC: 1358 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 239 AN: 3472

East Asian (EAS) AF: 0.0702 AC: 364 AN: 5188

South Asian (SAS) AF: 0.116 AC: 560 AN: 4824

European-Finnish (FIN) AF: 0.0563 AC: 598 AN: 10618

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0831 AC: 5656 AN: 68038

Other (OTH) AF: 0.0620 AC: 131 AN: 2112

Alfa AF: 0.0783 Hom.: 1032

Bravo AF: 0.0686

Asia WGS AF: 0.0920 AC: 319 AN: 3478

EpiCase AF: 0.0802

EpiControl AF: 0.0808

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.0
DANN	Benign	0.69
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs3732933; hg19: chr3-184911151; COSMIC: COSV51633315; COSMIC: COSV51633315;