3-185192345-G-T

Position:

• chr3-185192345-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001966.4(EHHADH):​c.2053C>A​(p.Gln685Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,874 control chromosomes in the GnomAD database, including 11,633 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (3401 hom., cov: 32)
  • Exomes 𝑓: 0.094 (8232 hom.)
• Consequence: EHHADH NM_001966.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013366491).
• BP6: Variant 3-185192345-G-T is Benign according to our data. Variant chr3-185192345-G-T is described in ClinVar as [Benign]. Clinvar id is 1262673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHHADH	NM_001966.4	c.2053C>A	p.Gln685Lys	missense_variant	7/7	ENST00000231887.8	NP_001957.2
EHHADH	NM_001166415.2	c.1765C>A	p.Gln589Lys	missense_variant	7/7		NP_001159887.1
EHHADH	XM_047447640.1	c.1429C>A	p.Gln477Lys	missense_variant	5/5		XP_047303596.1
EHHADH	XM_047447641.1	c.1429C>A	p.Gln477Lys	missense_variant	4/4		XP_047303597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHHADH	ENST00000231887.8	c.2053C>A	p.Gln685Lys	missense_variant	7/7	1	NM_001966.4	ENSP00000231887	P1
EHHADH	ENST00000456310.5	c.1765C>A	p.Gln589Lys	missense_variant	7/7	2		ENSP00000387746

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25202 AN: 151920 Hom.: 3373 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0701

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.109 AC: 27471 AN: 251078 Hom.: 2287 AF XY: 0.105 AC XY: 14309 AN XY: 135686

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0673

Gnomad EAS exome AF: 0.0717

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.0571

Gnomad NFE exome AF: 0.0811

Gnomad OTH exome AF: 0.0960

GnomAD4 exome AF: 0.0939 AC: 137307 AN: 1461836 Hom.: 8232 Cov.: 32 AF XY: 0.0939 AC XY: 68318 AN XY: 727222

Gnomad4 AFR exome AF: 0.381

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0699

Gnomad4 EAS exome AF: 0.0778

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.0559

Gnomad4 NFE exome AF: 0.0836

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.166 AC: 25289 AN: 152038 Hom.: 3401 Cov.: 32 AF XY: 0.165 AC XY: 12299 AN XY: 74316

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.0701

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0557

Gnomad4 NFE AF: 0.0848

Gnomad4 OTH AF: 0.130

Alfa AF: 0.0966 Hom.: 2540

Bravo AF: 0.180

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.0854 AC: 329

ESP6500AA AF: 0.358 AC: 1578

ESP6500EA AF: 0.0835 AC: 718

ExAC AF: 0.114 AC: 13807

Asia WGS AF: 0.119 AC: 414 AN: 3478

EpiCase AF: 0.0817

EpiControl AF: 0.0849

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.12	N;.
MutationTaster	Benign	0.88	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.17
Sift	Benign	0.90	T;T
Sift4G	Benign	0.88	T;T
Polyphen		0.0040	B;.
Vest4		0.031
MPC		0.095
ClinPred		0.0031	T
GERP RS		3.9
Varity_R		0.21
gMVP		0.64

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: rs11919970; hg19: chr3-184910133;