rs1051519

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005327.7(HADH):c.456G>T(p.Gln152His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,613,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 3 hom. )

Consequence

HADH
NM_005327.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 1.35

Variant links:

Genes affected

HADH (HGNC:4799): (hydroxyacyl-CoA dehydrogenase) This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]

HADH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02197808).

BP6

Variant 4-108019576-G-T is Benign according to our data. Variant chr4-108019576-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211127.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (284/152282) while in subpopulation NFE AF= 0.00378 (257/68028). AF 95% confidence interval is 0.0034. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7 link	c.456G>T	p.Gln152His	missense_variant	Exon 4 of 8	ENST00000309522.8	NP_005318.6	Q16836-1A0A140VK76
HADH	NM_001184705.4 link	c.456G>T	p.Gln152His	missense_variant	Exon 4 of 9		NP_001171634.3	Q16836-3
HADH	NM_001331027.2 link	c.468G>T	p.Gln156His	missense_variant	Exon 4 of 8		NP_001317956.2	B3KTT6
HADH	XR_007096395.1 link	n.500G>T		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 link	c.456G>T	p.Gln152His	missense_variant	Exon 4 of 8	1	NM_005327.7	ENSP00000312288.4		Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00378

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00180

AC:

452

AN:

251480

Hom.:

AF XY:

0.00175

AC XY:

238

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00379

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00259

AC:

3788

AN:

1461544

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

1807

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00329

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

AF:

0.00186

AC:

284

AN:

152282

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00378

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00333

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00203

AC:

246

EpiCase

AF:

0.00322

EpiControl

AF:

0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2020	This variant is associated with the following publications: (PMID: 8687463) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HADH: BP4, BS1 -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase;C1864948:Hyperinsulinemic hypoglycemia, familial, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 23, 2015

- -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 24, 2017

ACMG Criteria:PP3 (3 predictors), BP4 (7 predictors) -

Hyperinsulinemic hypoglycemia, familial, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

HADH-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;.;T;.;.

Eigen

Benign

-0.034

Eigen_PC

Benign

-0.0078

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.022

T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.6

.;L;L;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.8

.;.;N;N;.

REVEL

Uncertain

0.30

Sift

Benign

0.14

.;.;T;T;.

Sift4G

Benign

0.062

.;T;T;.;T

Polyphen

0.91

.;.;P;.;.

Vest4

0.36, 0.32, 0.32

MutPred

0.56

.;.;.;.;Gain of disorder (P = 0.0964);

MVP

0.84

MPC

0.23

ClinPred

0.032

GERP RS

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over