4-108014612-CTTTT-CTTTTTTT

Variant names:

• chr4-108014612-C-CTTT
• rs550348868
• NM_005327.7:c.419+37_419+39dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005327.7(HADH):​c.419+37_419+39dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000178 in 1,124,902 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: HADH NM_005327.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 0 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, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen
• hyperinsulinemic hypoglycemia, familial, 4

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7	c.419+37_419+39dupTTT		intron_variant	Intron 3 of 7	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.419+37_419+39dupTTT		intron_variant	Intron 3 of 8		NP_001171634.3
HADH	NM_001331027.2	c.431+37_431+39dupTTT		intron_variant	Intron 3 of 7		NP_001317956.2
HADH	XR_007096395.1	n.463+37_463+39dupTTT		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.419+37_419+39dupTTT		intron_variant	Intron 3 of 7	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000178 AC: 2 AN: 1124902 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 563842

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000393 AC: 1 AN: 25428

American (AMR) AF: 0.00 AC: 0 AN: 35210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21270

East Asian (EAS) AF: 0.00 AC: 0 AN: 32406

South Asian (SAS) AF: 0.00 AC: 0 AN: 69912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4716

European-Non Finnish (NFE) AF: 0.00000118 AC: 1 AN: 845880

Other (OTH) AF: 0.00 AC: 0 AN: 46976

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs550348868; hg19: chr4-108935768;