3-185192281-T-A

Position:

• chr3-185192281-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001966.4(EHHADH):​c.2117A>T​(p.Asn706Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,613,598 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (23 hom.)
• Consequence: EHHADH NM_001966.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.34

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0153059065).
• BP6: Variant 3-185192281-T-A is Benign according to our data. Variant chr3-185192281-T-A is described in ClinVar as [Benign]. Clinvar id is 501352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-185192281-T-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 646 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHHADH	NM_001966.4	c.2117A>T	p.Asn706Ile	missense_variant	7/7	ENST00000231887.8	NP_001957.2
EHHADH	NM_001166415.2	c.1829A>T	p.Asn610Ile	missense_variant	7/7		NP_001159887.1
EHHADH	XM_047447640.1	c.1493A>T	p.Asn498Ile	missense_variant	5/5		XP_047303596.1
EHHADH	XM_047447641.1	c.1493A>T	p.Asn498Ile	missense_variant	4/4		XP_047303597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHHADH	ENST00000231887.8	c.2117A>T	p.Asn706Ile	missense_variant	7/7	1	NM_001966.4	ENSP00000231887	P1
EHHADH	ENST00000456310.5	c.1829A>T	p.Asn610Ile	missense_variant	7/7	2		ENSP00000387746

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 645 AN: 151648 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00251

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00769

GnomAD3 exomes AF: 0.00443 AC: 1112 AN: 251024 Hom.: 5 AF XY: 0.00472 AC XY: 640 AN XY: 135722

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00744

Gnomad ASJ exome AF: 0.00725

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00537

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00453 AC: 6624 AN: 1461832 Hom.: 23 Cov.: 31 AF XY: 0.00452 AC XY: 3288 AN XY: 727226

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00747

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00328

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.00426 AC: 646 AN: 151766 Hom.: 1 Cov.: 32 AF XY: 0.00418 AC XY: 310 AN XY: 74140

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00251

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.00507

Gnomad4 OTH AF: 0.00761

Alfa AF: 0.00218 Hom.: 2

Bravo AF: 0.00490

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00418 AC: 507

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00753

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	Sep 01, 2022	EHHADH: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.015	T;T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.56	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.97	D;.
Vest4		0.44
MVP		0.81
MPC		0.40
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.53
gMVP		0.56

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: rs56056620; hg19: chr3-184910069; COSMIC: COSV99213458; COSMIC: COSV99213458;