3-185192254-A-G

Position:

• chr3-185192254-A-G

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.2144T>C​(p.Leu715Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,613,810 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.022 (115 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (115 hom.)
• Consequence: EHHADH NM_001966.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.42

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=0.0022486746).
• BP6: Variant 3-185192254-A-G is Benign according to our data. Variant chr3-185192254-A-G is described in ClinVar as [Benign]. Clinvar id is 775930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHHADH	NM_001966.4	c.2144T>C	p.Leu715Ser	missense_variant	7/7	ENST00000231887.8
EHHADH	NM_001166415.2	c.1856T>C	p.Leu619Ser	missense_variant	7/7
EHHADH	XM_047447640.1	c.1520T>C	p.Leu507Ser	missense_variant	5/5
EHHADH	XM_047447641.1	c.1520T>C	p.Leu507Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHHADH	ENST00000231887.8	c.2144T>C	p.Leu715Ser	missense_variant	7/7	1	NM_001966.4	P1
EHHADH	ENST00000456310.5	c.1856T>C	p.Leu619Ser	missense_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3361 AN: 152166 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00568 AC: 1425 AN: 250884 Hom.: 53 AF XY: 0.00449 AC XY: 609 AN XY: 135594

Gnomad AFR exome AF: 0.0805

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00227 AC: 3312 AN: 1461526 Hom.: 115 Cov.: 31 AF XY: 0.00202 AC XY: 1472 AN XY: 727078

Gnomad4 AFR exome AF: 0.0831

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.0221 AC: 3363 AN: 152284 Hom.: 115 Cov.: 32 AF XY: 0.0214 AC XY: 1597 AN XY: 74480

Gnomad4 AFR AF: 0.0773

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00436 Hom.: 37

Bravo AF: 0.0253

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0744 AC: 328

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00708 AC: 860

Asia WGS AF: 0.00491 AC: 17 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.53	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.17
Sift	Benign	0.064	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.92	P;.
Vest4		0.23
MVP		0.60
MPC		0.32
ClinPred		0.037	T
GERP RS		5.9
Varity_R		0.092
gMVP		0.72

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: rs11927618; hg19: chr3-184910042;