4-107989899-C-T

Variant names:

• chr4-107989899-C-T
• rs748286204
• NM_005327.7:c.-34C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005327.7(HADH):​c.-34C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000946 in 1,606,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: HADH NM_005327.7 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -2.19
• 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]

CYP2U1-AS1 (HGNC:54817): (CYP2U1 and SGMS2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-107989899-C-T is Benign according to our data. Variant chr4-107989899-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 900482.

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.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_005318.6	Q16836-1
	HADH	NM_005327.7	MANE Select	c.-34C>T		5_prime_UTR	Exon 1 of 8	NP_005318.6	Q16836-1
	HADH	NM_001184705.4		c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001171634.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000312288.4	Q16836-1
	HADH	ENST00000603302.5	TSL:1	c.-34C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000474560.1	Q16836-3
	HADH	ENST00000505878.4	TSL:1	c.144C>T	p.Pro48Pro	synonymous	Exon 1 of 9	ENSP00000425952.2	E9PF18

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000862 AC: 20 AN: 231956 AF XY: 0.0000946

Gnomad AFR exome AF: 0.000142

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000942 AC: 137 AN: 1454598 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 80 AN XY: 723060

African (AFR) AF: 0.0000301 AC: 1 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 44280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39440

South Asian (SAS) AF: 0.000519 AC: 44 AN: 84822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51308

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5644

European-Non Finnish (NFE) AF: 0.0000757 AC: 84 AN: 1109812

Other (OTH) AF: 0.0000333 AC: 2 AN: 60090

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74366

African (AFR) AF: 0.0000482 AC: 2 AN: 41478

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of 3-hydroxyacyl-CoA dehydrogenase (1)
-	-	1	Hyperinsulinemic hypoglycemia (1)
-	1	-	Hyperinsulinemic hypoglycemia, familial, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.4
DANN	Benign	0.82
PhyloP100		-2.2
PromoterAI		-0.0055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs748286204; hg19: chr4-108911055;