rs76476980

Positions:

• chr4-108027713-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_005327.7(HADH):​c.662G>A​(p.Arg221His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 1,609,822 control chromosomes in the GnomAD database, including 5 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 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:5
• Conservation: PhyloP100: 8.15

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.017106831).
• BP6: Variant 4-108027713-G-A is Benign according to our data. Variant chr4-108027713-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393392.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=5, Likely_pathogenic=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00331 (504/152126) while in subpopulation AFR AF= 0.0114 (474/41498). AF 95% confidence interval is 0.0106. There are 3 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADH	NM_005327.7	c.662G>A	p.Arg221His	missense_variant	6/8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.662G>A	p.Arg221His	missense_variant	6/9		NP_001171634.3
HADH	NM_001331027.2	c.674G>A	p.Arg225His	missense_variant	6/8		NP_001317956.2
HADH	XR_007096395.1	n.706G>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.662G>A	p.Arg221His	missense_variant	6/8	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152008 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000871 AC: 219 AN: 251434 Hom.: 0 AF XY: 0.000596 AC XY: 81 AN XY: 135896

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000340 AC: 496 AN: 1457696 Hom.: 2 Cov.: 28 AF XY: 0.000324 AC XY: 235 AN XY: 725508

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.000697

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152126 Hom.: 3 Cov.: 32 AF XY: 0.00300 AC XY: 223 AN XY: 74394

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00146 Hom.: 1

Bravo AF: 0.00393

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00105 AC: 128

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 4 Pathogenic:1 Benign:1

Likely pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	Feb 10, 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 rs76476980 in hyperinsulinemic hypoglycemia is yet to be ascertained. This variant is a potent moderate impact, deleterious variant with a CADD score of 31. This gene is found to be frequently associated with Hyperinsulinemic hypoglycemia as per recent evidence as well, with sufficient scientific evidence to support the reported classification. Loss of function mutations in HADH can potentially cause protein-induced hyperinsulinemic hypoglycemia -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 26, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	HADH: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2015	The R221H variant in the HADH gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Sequencing Project reports R221H was observed in 42/4406 alleles (0.95%) from individuals of African American background, indicating it may be a rare variant in this population. The R221H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense pathogenic variant in a nearby residues (Y226H) has been reported in the Human Gene Mutation Database in association with hyperinsulinemic hypoglycemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R221H as a variant of unknown significance. -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 26, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase;C1864948:Hyperinsulinemic hypoglycemia, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 12, 2018

ACMG criteria: PP3 (10 predictors), BS2 (27 cases and 24 controls in type2diabetesgenetics.org)=VUS NOTE: GeneDx also calls VUS -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	.;.;D;.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
MetaRNN	Benign	0.017	T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.6	.;H;H;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.9	.;.;D;.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;.;D;.
Sift4G	Pathogenic	0.0010	.;D;D;.;.;D
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.72, 0.71, 0.71
MVP		0.99
MPC		0.97
ClinPred		0.15	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs76476980; hg19: chr4-108948869; COSMIC: COSV104398723; COSMIC: COSV104398723;