4-108014444-T-G

Position:

chr4-108014444-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The ENST00000309522.8(HADH):c.275T>G(p.Phe92Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,614,044 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0051 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 56 hom. )

Consequence

HADH
ENST00000309522.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:8

Conservation

PhyloP100: 7.59

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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.022979915).

BP6

Variant 4-108014444-T-G is Benign according to our data. Variant chr4-108014444-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211126.We mark this variant Likely_benign, oryginal submissions are: {Likely_risk_allele=1, Benign=2, Likely_benign=6}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00514 (782/152184) while in subpopulation NFE AF= 0.00815 (554/67998). AF 95% confidence interval is 0.00759. There are 6 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HADH	NM_005327.7 linkuse as main transcript	c.275T>G	p.Phe92Cys	missense_variant	3/8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4 linkuse as main transcript	c.275T>G	p.Phe92Cys	missense_variant	3/9		NP_001171634.3
HADH	NM_001331027.2 linkuse as main transcript	c.287T>G	p.Phe96Cys	missense_variant	3/8		NP_001317956.2
HADH	XR_007096395.1 linkuse as main transcript	n.319T>G		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 linkuse as main transcript	c.275T>G	p.Phe92Cys	missense_variant	3/8	1	NM_005327.7	ENSP00000312288	P4	Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

783

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00540

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00816

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00546

AC:

1374

AN:

251490

Hom.:

AF XY:

0.00574

AC XY:

780

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00735

Gnomad FIN exome

AF:

0.00471

Gnomad NFE exome

AF:

0.00749

Gnomad OTH exome

AF:

0.00570

GnomAD4 exome

AF:

0.00664

AC:

9700

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00676

AC XY:

4915

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00264

Gnomad4 ASJ exome

AF:

0.00444

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00747

Gnomad4 FIN exome

AF:

0.00429

Gnomad4 NFE exome

AF:

0.00734

Gnomad4 OTH exome

AF:

0.00578

GnomAD4 genome

AF:

0.00514

AC:

782

AN:

152184

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

389

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00641

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00541

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.00815

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00670

Hom.:

Bravo

AF:

0.00418

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00532

AC:

646

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00682

EpiControl

AF:

0.00622

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	HADH: BS2 -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hyperinsulinemic hypoglycemia, familial, 4

Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Feb 21, 2024

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 rs61735992 in congenital hyperinsulinism is yet to be ascertained. This variant is a potent moderate impact, deleterious variant with a CADD score of 29. This gene is found to be frequently associated with congenital hyperinsulinism as per recent evidence as well, with sufficient scientific evidence to support the reported classification. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 13, 2021

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

ACMG criteria: PP3 (REVEL=0.71 + 8 predictors; not using BP4/2 predictors), BS2 (78 cases and 88 controls in type2diabetesgenetics.org; 8 homozygotes in gnomAD), BS1 (0.5% overall MAF in gnomAD)= benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

.;.;D;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.023

T;T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.4

.;M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.3

.;.;D;D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0050

.;.;D;D;.

Sift4G

Uncertain

0.038

.;D;D;.;T

Polyphen

1.0

.;.;D;.;.

Vest4

0.82, 0.80, 0.89

MVP

0.93

MPC

1.0

ClinPred

0.037

GERP RS

5.8

Varity_R

0.95

gMVP

0.67

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