4-107989881-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1 BS1_Supporting

The ENST00000505878.4(HADH):c.127del(p.Arg43AlafsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,597,368 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain risk allele (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: HADH ENST00000505878.4 frameshift
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: -2.08

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000768 (117/152312) while in subpopulation AMR AF= 0.00314 (48/15304). AF 95% confidence interval is 0.00243. There are 1 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADH	NM_005327.7			upstream_gene_variant		ENST00000309522.8
HADH	NM_001184705.4			upstream_gene_variant
HADH	XR_007096395.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADH	ENST00000309522.8			upstream_gene_variant		1	NM_005327.7	P4

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000489 AC: 106 AN: 216574 Hom.: 0 AF XY: 0.000547 AC XY: 65 AN XY: 118832

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000924

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000547

Gnomad FIN exome AF: 0.0000535

Gnomad NFE exome AF: 0.000603

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.000763 AC: 1103 AN: 1445056 Hom.: 2 Cov.: 31 AF XY: 0.000737 AC XY: 529 AN XY: 717652

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000901

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000563

Gnomad4 FIN exome AF: 0.0000806

Gnomad4 NFE exome AF: 0.000877

Gnomad4 OTH exome AF: 0.000619

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000706

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hyperinsulinism, Dominant/Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hyperinsulinemic hypoglycemia Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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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 rs574132278 in congenital hyperinsulinism is yet to be ascertained. -

Computational scores

Source: dbNSFP v4.3

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: rs574132278; hg19: chr4-108911037;