chr4-108014612-CT-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 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

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

Our verdict: Benign. The variant received -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: {Uncertain_significance=1, Likely_benign=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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.419+25delT		intron_variant	Intron 3 of 7	1	NM_005327.7	ENSP00000312288.4

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

Gnomad4 AFR exome AF: 0.246 AC: 4778 AN: 19434

Gnomad4 AMR exome AF: 0.261 AC: 6019 AN: 23104

Gnomad4 ASJ exome AF: 0.302 AC: 3968 AN: 13138

Gnomad4 EAS exome AF: 0.291 AC: 5479 AN: 18810

Gnomad4 SAS exome AF: 0.297 AC: 11490 AN: 38672

Gnomad4 FIN exome AF: 0.267 AC: 7752 AN: 28996

Gnomad4 NFE exome AF: 0.220 AC: 141864 AN: 645794

Gnomad4 Remaining exome AF: 0.248 AC: 8203 AN: 33050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (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

Gnomad4 AFR AF: 0.00209 AC: 0.00209002 AN: 0.00209002

Gnomad4 AMR AF: 0.00253 AC: 0.00252732 AN: 0.00252732

Gnomad4 ASJ AF: 0.00117 AC: 0.00117165 AN: 0.00117165

Gnomad4 EAS AF: 0.00139 AC: 0.00139387 AN: 0.00139387

Gnomad4 SAS AF: 0.00436 AC: 0.0043592 AN: 0.0043592

Gnomad4 FIN AF: 0.0110 AC: 0.0110366 AN: 0.0110366

Gnomad4 NFE AF: 0.00312 AC: 0.00311574 AN: 0.00311574

Gnomad4 OTH AF: 0.00100 AC: 0.001 AN: 0.001

Alfa AF: 0.114 Hom.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperinsulinemic hypoglycemia Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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

Apr 29, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

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