4-107989895-T-C

Position:

chr4-107989895-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000505878.4(HADH):c.140T>C(p.Leu47Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 1,605,240 control chromosomes in the GnomAD database, including 8,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2243 hom., cov: 33)

Exomes 𝑓: 0.081 ( 6061 hom. )

Consequence

HADH
ENST00000505878.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.51

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004533261).

BP6

Variant 4-107989895-T-C is Benign according to our data. Variant chr4-107989895-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 347129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
HADH	NM_005327.7 linkuse as main transcript	c.-38T>C	5_prime_UTR_variant	1/8	ENST00000309522.8
HADH	NM_001184705.4 linkuse as main transcript	c.-38T>C	5_prime_UTR_variant	1/9
HADH	XR_007096395.1 linkuse as main transcript	n.7T>C	non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADH	ENST00000309522.8 linkuse as main transcript	c.-38T>C		5_prime_UTR_variant	1/8	1	NM_005327.7	P4	Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20301

AN:

152180

Hom.:

2243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.304

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0687

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.0282

Gnomad SAS

AF:

0.0987

Gnomad FIN

AF:

0.0371

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.0775

Gnomad OTH

AF:

0.107

GnomAD3 exomes

AF:

0.0757

AC:

17394

AN:

229702

Hom.:

1166

AF XY:

0.0770

AC XY:

9676

AN XY:

125666

show subpopulations

Gnomad AFR exome

AF:

0.297

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.0243

Gnomad EAS exome

AF:

0.0246

Gnomad SAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.0384

Gnomad NFE exome

AF:

0.0727

Gnomad OTH exome

AF:

0.0669

GnomAD4 exome

AF:

0.0807

AC:

117282

AN:

1452942

Hom.:

6061

Cov.:

AF XY:

0.0811

AC XY:

58578

AN XY:

722106

show subpopulations

Gnomad4 AFR exome

AF:

0.306

Gnomad4 AMR exome

AF:

0.0410

Gnomad4 ASJ exome

AF:

0.0246

Gnomad4 EAS exome

AF:

0.0318

Gnomad4 SAS exome

AF:

0.103

Gnomad4 FIN exome

AF:

0.0400

Gnomad4 NFE exome

AF:

0.0787

Gnomad4 OTH exome

AF:

0.0814

GnomAD4 genome

AF:

0.133

AC:

20320

AN:

152298

Hom.:

2243

Cov.:

AF XY:

0.130

AC XY:

9649

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.303

Gnomad4 AMR

AF:

0.0685

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.0281

Gnomad4 SAS

AF:

0.0983

Gnomad4 FIN

AF:

0.0371

Gnomad4 NFE

AF:

0.0775

Gnomad4 OTH

AF:

0.106

Alfa

AF:

0.0986

Hom.:

216

Bravo

AF:

0.141

TwinsUK

AF:

0.0833

AC:

309

ALSPAC

AF:

0.0786

AC:

303

ESP6500AA

AF:

0.283

AC:

1244

ESP6500EA

AF:

0.0733

AC:

630

ExAC

AF:

0.0799

AC:

9620

Asia WGS

AF:

0.0750

AC:

262

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hyperinsulinemic hypoglycemia

Benign:1

Likely benign, 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 rs17550794 in congenital hyperinsulinism is yet to be ascertained. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hyperinsulinemic hypoglycemia, familial, 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.6

DANN

Benign

0.52

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0045

MutationTaster

Benign

1.0

P;P

GERP RS

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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