3-185192290-G-A

Position:

• chr3-185192290-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.81

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]

ACMG classification

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: {Uncertain_significance=1, Benign=2}.
• 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	UniProt
EHHADH	NM_001966.4	c.2108C>T	p.Ser703Phe	missense_variant	7/7	ENST00000231887.8
EHHADH	NM_001166415.2	c.1820C>T	p.Ser607Phe	missense_variant	7/7
EHHADH	XM_047447640.1	c.1484C>T	p.Ser495Phe	missense_variant	5/5
EHHADH	XM_047447641.1	c.1484C>T	p.Ser495Phe	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHHADH	ENST00000231887.8	c.2108C>T	p.Ser703Phe	missense_variant	7/7	1	NM_001966.4	P1
EHHADH	ENST00000456310.5	c.1820C>T	p.Ser607Phe	missense_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1286 AN: 152178 Hom.: 9 Cov.: 32

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.: 25 AF XY: 0.00979 AC XY: 1328 AN XY: 135704

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.: 31 AF XY: 0.0123 AC XY: 8951 AN XY: 727232

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.: 9 Cov.: 32 AF XY: 0.00786 AC XY: 585 AN XY: 74472

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.: 22

Bravo AF: 0.00883

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0144 AC: 124

ExAC AF: 0.00973 AC: 1181

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0187

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

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	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.67	D;D
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs55752621; hg19: chr3-184910078; COSMIC: COSV99040005; COSMIC: COSV99040005;