3-185192256-G-T

Position:

• chr3-185192256-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001966.4(EHHADH):​c.2142C>A​(p.Ser714Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: EHHADH NM_001966.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093818605).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHHADH	NM_001966.4	c.2142C>A	p.Ser714Arg	missense_variant	7/7	ENST00000231887.8
EHHADH	NM_001166415.2	c.1854C>A	p.Ser618Arg	missense_variant	7/7
EHHADH	XM_047447640.1	c.1518C>A	p.Ser506Arg	missense_variant	5/5
EHHADH	XM_047447641.1	c.1518C>A	p.Ser506Arg	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHHADH	ENST00000231887.8	c.2142C>A	p.Ser714Arg	missense_variant	7/7	1	NM_001966.4	P1
EHHADH	ENST00000456310.5	c.1854C>A	p.Ser618Arg	missense_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461608 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2023

The c.2142C>A (p.S714R) alteration is located in exon 7 (coding exon 7) of the EHHADH gene. This alteration results from a C to A substitution at nucleotide position 2142, causing the serine (S) at amino acid position 714 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.56	N;.
MutationTaster	Benign	0.88	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.044
Sift	Benign	0.15	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0050	B;.
Vest4		0.13
MutPred		0.42		Gain of MoRF binding (P = 0.0026);.;
MVP		0.20
MPC		0.089
ClinPred		0.046	T
GERP RS		1.9
Varity_R		0.066
gMVP		0.61

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: rs917179166; hg19: chr3-184910044;