4-108014612-CTTTT-CTTT

Position:

• chr4-108014612-CTTTT-CTTT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000309522.8(HADH):​c.419+39del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 145,440 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.23 (165 hom.)
  • Failed GnomAD Quality Control
• Consequence: HADH ENST00000309522.8 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.11

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 -9 ACMG points.

• BP6: Variant 4-108014612-CT-C is Benign according to our data. Variant chr4-108014612-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435392.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00316 (460/145440) while in subpopulation SAS AF= 0.00436 (20/4588). AF 95% confidence interval is 0.00289. There are 2 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADH	NM_005327.7	c.419+39del		intron_variant		ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.419+39del		intron_variant			NP_001171634.3
HADH	NM_001331027.2	c.431+39del		intron_variant			NP_001317956.2
HADH	XR_007096395.1	n.463+39del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.419+39del		intron_variant		1	NM_005327.7	ENSP00000312288	P4

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 459 AN: 145380 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00253

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.00413

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00101

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.231 AC: 190128 AN: 824632 Hom.: 165 Cov.: 0 AF XY: 0.238 AC XY: 95865 AN XY: 403542

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.291

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.267

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.248

GnomAD4 genome AF: 0.00316 AC: 460 AN: 145440 Hom.: 2 Cov.: 32 AF XY: 0.00341 AC XY: 241 AN XY: 70618

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00253

Gnomad4 ASJ AF: 0.00117

Gnomad4 EAS AF: 0.00139

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.00312

Gnomad4 OTH AF: 0.00100

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperinsulinemic hypoglycemia Uncertain:1

Uncertain significance, 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 rs550348868 in congenital hyperinsulinism is yet to be ascertained. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 29, 2016

- -

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: rs550348868; hg19: chr4-108935768;