chr4-107989868-G-A

Position:

chr4-107989868-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000505878.4(HADH):c.113G>A(p.Arg38His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,581,044 control chromosomes in the GnomAD database, including 70 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 0.012 ( 38 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 32 hom. )

Consequence

HADH
ENST00000505878.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.39

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=0.0023628771).

BP6

Variant 4-107989868-G-A is Benign according to our data. Variant chr4-107989868-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0121 (1844/152320) while in subpopulation AFR AF= 0.0424 (1765/41584). AF 95% confidence interval is 0.0408. There are 38 homozygotes in gnomad4. There are 854 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
HADH	NM_005327.7 link	c.-65G>A	upstream_gene_variant	ENST00000309522.8	NP_005318.6	Q16836-1A0A140VK76
HADH	NM_001184705.4 link	c.-65G>A	upstream_gene_variant		NP_001171634.3	Q16836-3
HADH	XR_007096395.1 link	n.-21G>A	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 link	c.-65G>A		upstream_gene_variant		1	NM_005327.7	ENSP00000312288.4		Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1845

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0426

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00278

AC:

545

AN:

196208

Hom.:

AF XY:

0.00212

AC XY:

228

AN XY:

107474

show subpopulations

Gnomad AFR exome

AF:

0.0458

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.000112

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000388

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000597

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.00106

AC:

1511

AN:

1428724

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

640

AN XY:

708666

show subpopulations

Gnomad4 AFR exome

AF:

0.0391

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.000118

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000366

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000273

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.0121

AC:

1844

AN:

152320

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

854

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0424

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.000908

Hom.:

Bravo

AF:

0.0132

ExAC

AF:

0.00345

AC:

411

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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 rs28703310 in congenital hyperinsulinism is yet to be ascertained. -

Hyperinsulinemic hypoglycemia, familial, 4

Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.9

DANN

Benign

0.77

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0024

GERP RS

-3.1

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