4-108014612-CTTTT-CTTT

Variant names:

• chr4-108014612-CT-C
• rs550348868
• NM_005327.7:c.419+39delT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005327.7(HADH):​c.419+39delT 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 NM_005327.7 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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: Likely_benign. The variant received -5 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 VariationId is 435392.
• BS2: High Homozygotes in GnomAd4 at 2 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.419+39delT		intron	N/A	NP_005318.6
	HADH	NM_001184705.4		c.419+39delT		intron	N/A	NP_001171634.3
	HADH	NM_001331027.2		c.431+39delT		intron	N/A	NP_001317956.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.419+25delT		intron	N/A	ENSP00000312288.4
	HADH	ENST00000505878.4	TSL:1	c.596+25delT		intron	N/A	ENSP00000425952.2
	HADH	ENST00000603302.5	TSL:1	c.419+25delT		intron	N/A	ENSP00000474560.1

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

GnomAD2 exomes AF: 0.259 AC: 31566 AN: 122084 AF XY: 0.268

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.267

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

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

African (AFR) AF: 0.246 AC: 4778 AN: 19434

American (AMR) AF: 0.261 AC: 6019 AN: 23104

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 3968 AN: 13138

East Asian (EAS) AF: 0.291 AC: 5479 AN: 18810

South Asian (SAS) AF: 0.297 AC: 11490 AN: 38672

European-Finnish (FIN) AF: 0.267 AC: 7752 AN: 28996

Middle Eastern (MID) AF: 0.158 AC: 575 AN: 3634

European-Non Finnish (NFE) AF: 0.220 AC: 141864 AN: 645794

Other (OTH) AF: 0.248 AC: 8203 AN: 33050

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

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

African (AFR) AF: 0.00209 AC: 82 AN: 39234

American (AMR) AF: 0.00253 AC: 37 AN: 14640

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 4 AN: 3414

East Asian (EAS) AF: 0.00139 AC: 7 AN: 5022

South Asian (SAS) AF: 0.00436 AC: 20 AN: 4588

European-Finnish (FIN) AF: 0.0110 AC: 102 AN: 9242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00312 AC: 206 AN: 66116

Other (OTH) AF: 0.00100 AC: 2 AN: 2000

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.114 Hom.: 24

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperinsulinemic hypoglycemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs550348868; hg19: chr4-108935768; COSMIC: COSV58849075;