3-185192290-G-A

Position:

chr3-185192290-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001966.4(EHHADH):c.2108C>T(p.Ser703Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0119 in 1,614,160 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0084 ( 9 hom., cov: 32)

Exomes 𝑓: 0.012 ( 132 hom. )

Consequence

EHHADH
NM_001966.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.81

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045408607).

BP6

Variant 3-185192290-G-A is Benign according to our data. Variant chr3-185192290-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 774610.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0123 (18002/1461864) while in subpopulation MID AF= 0.0182 (105/5766). AF 95% confidence interval is 0.0154. There are 132 homozygotes in gnomad4_exome. There are 8951 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1283 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EHHADH	NM_001966.4 linkuse as main transcript	c.2108C>T	p.Ser703Phe	missense_variant	7/7	ENST00000231887.8	NP_001957.2
EHHADH	NM_001166415.2 linkuse as main transcript	c.1820C>T	p.Ser607Phe	missense_variant	7/7		NP_001159887.1
EHHADH	XM_047447640.1 linkuse as main transcript	c.1484C>T	p.Ser495Phe	missense_variant	5/5		XP_047303596.1
EHHADH	XM_047447641.1 linkuse as main transcript	c.1484C>T	p.Ser495Phe	missense_variant	4/4		XP_047303597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHHADH	ENST00000231887.8 linkuse as main transcript	c.2108C>T	p.Ser703Phe	missense_variant	7/7	1	NM_001966.4	ENSP00000231887	P1	Q08426-1
EHHADH	ENST00000456310.5 linkuse as main transcript	c.1820C>T	p.Ser607Phe	missense_variant	7/7	2		ENSP00000387746		Q08426-2

Frequencies

GnomAD3 genomes

AF:

0.00845

AC:

1286

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00919

AC:

2306

AN:

250920

Hom.:

AF XY:

0.00979

AC XY:

1328

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00280

Gnomad AMR exome

AF:

0.00721

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00755

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.0123

AC:

18002

AN:

1461864

Hom.:

132

Cov.:

AF XY:

0.0123

AC XY:

8951

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00236

Gnomad4 AMR exome

AF:

0.00727

Gnomad4 ASJ exome

AF:

0.00474

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00768

Gnomad4 FIN exome

AF:

0.00330

Gnomad4 NFE exome

AF:

0.0143

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.00842

AC:

1283

AN:

152296

Hom.:

Cov.:

AF XY:

0.00786

AC XY:

585

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.00954

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.0142

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.00883

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0144

AC:

124

ExAC

AF:

0.00973

AC:

1181

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0175

EpiControl

AF:

0.0187

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	EHHADH: BS1, BS2 -

Chronic kidney disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PP3, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0045

T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

0.67

D;D

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.94

P;.

Vest4

0.088

MVP

0.81

MPC

0.22

ClinPred

0.019

GERP RS

5.0

Varity_R

0.37

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over