rs76476980

Variant names:

• chr4-108027713-G-A
• rs76476980
• NM_005327.7:c.662G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP4_Strong BS1_Supporting 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221C) has been classified as Uncertain significance.

• 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• 3-hydroxyacyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• hyperinsulinemic hypoglycemia, familial, 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.017106831).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005327.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	NM_005327.7	MANE Select	c.662G>A	p.Arg221His	missense	Exon 6 of 8	NP_005318.6	Q16836-1
	HADH	NM_001184705.4		c.662G>A	p.Arg221His	missense	Exon 6 of 9	NP_001171634.3
	HADH	NM_001331027.2		c.674G>A	p.Arg225His	missense	Exon 6 of 8	NP_001317956.2	A0A0D9SFP2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.662G>A	p.Arg221His	missense	Exon 6 of 8	ENSP00000312288.4	Q16836-1
	HADH	ENST00000505878.4	TSL:1	c.839G>A	p.Arg280His	missense	Exon 6 of 9	ENSP00000425952.2	E9PF18
	HADH	ENST00000603302.5	TSL:1	c.662G>A	p.Arg221His	missense	Exon 6 of 9	ENSP00000474560.1	Q16836-3

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

GnomAD2 exomes AF: 0.000871 AC: 219 AN: 251434 AF XY: 0.000596

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 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

African (AFR) AF: 0.0113 AC: 377 AN: 33396

American (AMR) AF: 0.000604 AC: 27 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5754

European-Non Finnish (NFE) AF: 0.0000325 AC: 36 AN: 1108198

Other (OTH) AF: 0.000697 AC: 42 AN: 60272

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

African (AFR) AF: 0.0114 AC: 474 AN: 41498

American (AMR) AF: 0.00131 AC: 20 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67988

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00166 Hom.: 3

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Deficiency of 3-hydroxyacyl-CoA dehydrogenase (2)
1	-	1	Hyperinsulinemic hypoglycemia, familial, 4 (2)
-	1	1	not provided (2)
-	1	-	Deficiency of 3-hydroxyacyl-CoA dehydrogenase;C1864948:Hyperinsulinemic hypoglycemia, familial, 4 (1)
-	1	-	Monogenic diabetes (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.72
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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

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