rs36030668

Positions:

chr4-108034293-A-G

Variant summary

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

The NM_005327.7(HADH):c.881A>G(p.Asn294Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,613,920 control chromosomes in the GnomAD database, including 18 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0068 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 9 hom. )

Consequence

HADH
NM_005327.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:5O:1

Conservation

PhyloP100: 4.27

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=0.007502228).

BP6

Variant 4-108034293-A-G is Benign according to our data. Variant chr4-108034293-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393393.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_risk_allele=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00679 (1034/152358) while in subpopulation AFR AF= 0.0239 (993/41588). AF 95% confidence interval is 0.0226. There are 9 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HADH	NM_005327.7 linkuse as main transcript	c.881A>G	p.Asn294Ser	missense_variant	8/8	ENST00000309522.8
HADH	NM_001184705.4 linkuse as main transcript	c.932A>G	p.Asn311Ser	missense_variant	9/9
HADH	NM_001331027.2 linkuse as main transcript	c.893A>G	p.Asn298Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADH	ENST00000309522.8 linkuse as main transcript	c.881A>G	p.Asn294Ser	missense_variant	8/8	1	NM_005327.7	P4	Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.00675

AC:

1027

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00180

AC:

453

AN:

251480

Hom.:

AF XY:

0.00120

AC XY:

163

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000626

AC:

915

AN:

1461562

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

387

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0231

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00114

GnomAD4 genome

AF:

0.00679

AC:

1034

AN:

152358

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

476

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0239

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.00778

ESP6500AA

AF:

0.0218

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00222

AC:

269

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 29, 2019

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Nov 21, 2018

ACMG criteria: BA1(2 % MAF in Africans), BS2 (5 homo in gnomAD, 64 T2DM control~cases) [BP4 (4 predictors), PP3 (6 predictors), REVEL: 0.283--conflicting data, no predictors used]=benign -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2019

- -

Hyperinsulinemic hypoglycemia

Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs36030668 in congenital hyperinsulinism is yet to be ascertained. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

.;.;T;.;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

MetaRNN

Benign

0.0075

T;T;T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

-0.16

.;.;N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.9

.;.;D;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.035

.;.;D;.;.;.

Sift4G

Benign

0.38

.;T;T;.;.;T

Polyphen

0.0010

.;.;B;.;.;.

Vest4

0.10, 0.090, 0.11

MVP

0.88

MPC

0.19

ClinPred

0.036

GERP RS

3.1

Varity_R

0.13

gMVP

0.82

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