rs61735992

chr4-108014444-T-G

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.275T>G(p.Phe92Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,614,044 control chromosomes in the GnomAD database, including 62 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 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (56 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:8
• Conservation: PhyloP100: 7.59

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.022979915).
• BP6: Variant 4-108014444-T-G is Benign according to our data. Variant chr4-108014444-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211126.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Likely_risk_allele=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00514 (782/152184) while in subpopulation NFE AF= 0.00815 (554/67998). AF 95% confidence interval is 0.00759. There are 6 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADH	NM_005327.7	c.275T>G	p.Phe92Cys	missense_variant	3/8	ENST00000309522.8
HADH	NM_001184705.4	c.275T>G	p.Phe92Cys	missense_variant	3/9
HADH	NM_001331027.2	c.287T>G	p.Phe96Cys	missense_variant	3/8
HADH	XR_007096395.1	n.319T>G		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADH	ENST00000309522.8	c.275T>G	p.Phe92Cys	missense_variant	3/8	1	NM_005327.7	P4

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152066 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00546 AC: 1374 AN: 251490 Hom.: 5 AF XY: 0.00574 AC XY: 780 AN XY: 135918

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.00749

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00664 AC: 9700 AN: 1461860 Hom.: 56 Cov.: 32 AF XY: 0.00676 AC XY: 4915 AN XY: 727234

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00747

Gnomad4 FIN exome AF: 0.00429

Gnomad4 NFE exome AF: 0.00734

Gnomad4 OTH exome AF: 0.00578

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152184 Hom.: 6 Cov.: 32 AF XY: 0.00523 AC XY: 389 AN XY: 74418

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00541

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00815

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00670 Hom.: 4

Bravo AF: 0.00418

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00532 AC: 646

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00622

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HADH: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2022	- -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hyperinsulinemic hypoglycemia, familial, 4 Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Feb 21, 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 rs61735992 in congenital hyperinsulinism is yet to be ascertained. This variant is a potent moderate impact, deleterious variant with a CADD score of 29. This gene is found to be frequently associated with congenital hyperinsulinism as per recent evidence as well, with sufficient scientific evidence to support the reported classification. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 13, 2021

- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

ACMG criteria: PP3 (REVEL=0.71 + 8 predictors; not using BP4/2 predictors), BS2 (78 cases and 88 controls in type2diabetesgenetics.org; 8 homozygotes in gnomAD), BS1 (0.5% overall MAF in gnomAD)= benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	27
Dann	Uncertain	0.98
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
REVEL	Pathogenic	0.70
Polyphen		1.0	.;.;D;.;.
Vest4		0.82, 0.80, 0.89
MVP		0.93
MPC		1.0
ClinPred		0.037	T
GERP RS		5.8
Varity_R		0.95
gMVP		0.67

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

Other links and lift over

dbSNP: rs61735992; hg19: chr4-108935600; COSMIC: COSV58849932;