3-185192300-T-G

Position:

• chr3-185192300-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001966.4(EHHADH):​c.2098A>C​(p.Lys700Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EHHADH NM_001966.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2966946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHHADH	NM_001966.4	c.2098A>C	p.Lys700Gln	missense_variant	7/7	ENST00000231887.8	NP_001957.2
EHHADH	NM_001166415.2	c.1810A>C	p.Lys604Gln	missense_variant	7/7		NP_001159887.1
EHHADH	XM_047447640.1	c.1474A>C	p.Lys492Gln	missense_variant	5/5		XP_047303596.1
EHHADH	XM_047447641.1	c.1474A>C	p.Lys492Gln	missense_variant	4/4		XP_047303597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHHADH	ENST00000231887.8	c.2098A>C	p.Lys700Gln	missense_variant	7/7	1	NM_001966.4	ENSP00000231887	P1
EHHADH	ENST00000456310.5	c.1810A>C	p.Lys604Gln	missense_variant	7/7	2		ENSP00000387746

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 26, 2022

The c.2098A>C (p.K700Q) alteration is located in exon 7 (coding exon 7) of the EHHADH gene. This alteration results from a A to C substitution at nucleotide position 2098, causing the lysine (K) at amino acid position 700 to be replaced by a glutamine (Q). 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	0.090
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.087	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.69	P;.
Vest4		0.36
MutPred		0.41		Loss of ubiquitination at K700 (P = 0.0092);.;
MVP		0.54
MPC		0.22
ClinPred		0.71	D
GERP RS		5.9
Varity_R		0.35
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-184910088;