4-107989862-C-T

Position:

chr4-107989862-C-T

Variant summary

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

The ENST00000505878.4(HADH):c.107C>T(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00988 in 1,571,448 control chromosomes in the GnomAD database, including 199 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 0.021 ( 73 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 126 hom. )

Consequence

HADH
ENST00000505878.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.07

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=0.0022934377).

BP6

Variant 4-107989862-C-T is Benign according to our data. Variant chr4-107989862-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 347126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-107989862-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
HADH	NM_005327.7 link	c.-71C>T	upstream_gene_variant	ENST00000309522.8	NP_005318.6	Q16836-1A0A140VK76
HADH	NM_001184705.4 link	c.-71C>T	upstream_gene_variant		NP_001171634.3	Q16836-3
HADH	XR_007096395.1 link	n.-27C>T	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 link	c.-71C>T		upstream_gene_variant		1	NM_005327.7	ENSP00000312288.4		Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3212

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0556

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00503

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00661

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0115

AC:

2170

AN:

188742

Hom.:

AF XY:

0.0113

AC XY:

1162

AN XY:

103260

show subpopulations

Gnomad AFR exome

AF:

0.0544

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.00205

Gnomad EAS exome

AF:

0.00334

Gnomad SAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.00625

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.00866

AC:

12291

AN:

1419136

Hom.:

126

Cov.:

AF XY:

0.00867

AC XY:

6101

AN XY:

703672

show subpopulations

Gnomad4 AFR exome

AF:

0.0573

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00528

Gnomad4 SAS exome

AF:

0.0199

Gnomad4 FIN exome

AF:

0.00695

Gnomad4 NFE exome

AF:

0.00629

Gnomad4 OTH exome

AF:

0.0126

GnomAD4 genome

AF:

0.0212

AC:

3231

AN:

152312

Hom.:

Cov.:

AF XY:

0.0209

AC XY:

1560

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0560

Gnomad4 AMR

AF:

0.0149

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00504

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.00660

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0238

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00752

AC:

ExAC

AF:

0.0109

AC:

1297

Asia WGS

AF:

0.0120

AC:

AN:

3478

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 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 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 rs760202 in congenital hyperinsulinism is yet to be ascertained. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hyperinsulinemic hypoglycemia, familial, 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.2

DANN

Benign

0.81

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0023

GERP RS

-1.4

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