rs398124646

Variant names:

• chr3-185254016-C-T
• rs398124646
• NM_001966.4:c.7G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001966.4(EHHADH):​c.7G>A​(p.Glu3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EHHADH NM_001966.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.32
• Publications: 5 publications found

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]

EHHADH Gene-Disease associations (from GenCC):

• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi renotubular syndrome 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-185254016-C-T is Pathogenic according to our data. Variant chr3-185254016-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 96711.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36598387). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHHADH	NM_001966.4	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 7	ENST00000231887.8	NP_001957.2
EHHADH	NM_001166415.2	c.-405G>A		5_prime_UTR_variant	Exon 1 of 7		NP_001159887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHHADH	ENST00000231887.8	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 7	1	NM_001966.4	ENSP00000231887.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fanconi renotubular syndrome 3 Pathogenic:1

Jan 09, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.067
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.74	N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.27	T;D
Sift4G	Benign	0.28	T;D
Polyphen		0.32	B;.
Vest4		0.60
MutPred		0.29		Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);
MVP		0.21
MPC		0.094
ClinPred		0.88	D
GERP RS		4.8
PromoterAI		-0.64	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.17
gMVP		0.61
Mutation Taster		=32/68	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398124646; hg19: chr3-184971804;