rs17511214

Positions:

Variant summary

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

The NM_005327.7(HADH):c.636+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,455,470 control chromosomes in the GnomAD database, including 2,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 131 hom., cov: 33)

Exomes 𝑓: 0.051 ( 1919 hom. )

Consequence

HADH
NM_005327.7 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.15

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 (BayesDel_noAF=-0.64).

BP6

Variant 4-108023576-G-A is Benign according to our data. Variant chr4-108023576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
HADH	NM_005327.7 linkuse as main transcript	c.636+13G>A	intron_variant	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4 linkuse as main transcript	c.636+13G>A	intron_variant		NP_001171634.3
HADH	NM_001331027.2 linkuse as main transcript	c.648+13G>A	intron_variant		NP_001317956.2
HADH	XR_007096395.1 linkuse as main transcript	n.680+13G>A	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 linkuse as main transcript	c.636+13G>A		intron_variant		1	NM_005327.7	ENSP00000312288	P4	Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.0406

AC:

6181

AN:

152160

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0413

Gnomad ASJ

AF:

0.0700

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.0700

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0570

Gnomad OTH

AF:

0.0512

GnomAD3 exomes

AF:

0.0408

AC:

10262

AN:

251394

Hom.:

290

AF XY:

0.0413

AC XY:

5616

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00733

Gnomad AMR exome

AF:

0.0233

Gnomad ASJ exome

AF:

0.0636

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0198

Gnomad FIN exome

AF:

0.0666

Gnomad NFE exome

AF:

0.0562

Gnomad OTH exome

AF:

0.0417

GnomAD4 exome

AF:

0.0507

AC:

66023

AN:

1303194

Hom.:

1919

Cov.:

AF XY:

0.0499

AC XY:

32770

AN XY:

656988

show subpopulations

Gnomad4 AFR exome

AF:

0.00781

Gnomad4 AMR exome

AF:

0.0258

Gnomad4 ASJ exome

AF:

0.0602

Gnomad4 EAS exome

AF:

0.0000512

Gnomad4 SAS exome

AF:

0.0197

Gnomad4 FIN exome

AF:

0.0658

Gnomad4 NFE exome

AF:

0.0570

Gnomad4 OTH exome

AF:

0.0481

GnomAD4 genome

AF:

0.0406

AC:

6178

AN:

152276

Hom.:

131

Cov.:

AF XY:

0.0403

AC XY:

2999

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0103

Gnomad4 AMR

AF:

0.0412

Gnomad4 ASJ

AF:

0.0700

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.0700

Gnomad4 NFE

AF:

0.0570

Gnomad4 OTH

AF:

0.0507

Alfa

AF:

0.0496

Hom.:

Bravo

AF:

0.0372

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Hyperinsulinemic hypoglycemia, familial, 1

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 rs17511214 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_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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