chr4-108009883-T-C

Variant names:

• chr4-108009883-T-C
• rs4956145
• NM_005327.7:c.257T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005327.7(HADH):​c.257T>C​(p.Leu86Pro) variant causes a missense change. The variant allele was found at a frequency of 0.914 in 1,607,364 control chromosomes in the GnomAD database, including 674,453 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57994 hom., cov: 29)
  • Exomes 𝑓: 0.92 (616459 hom.)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.87

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.211664E-7).
• BP6: Variant 4-108009883-T-C is Benign according to our data. Variant chr4-108009883-T-C is described in ClinVar as [Benign]. Clinvar id is 167162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-108009883-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7	c.257T>C	p.Leu86Pro	missense_variant	Exon 2 of 8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.257T>C	p.Leu86Pro	missense_variant	Exon 2 of 9		NP_001171634.3
HADH	NM_001331027.2	c.269T>C	p.Leu90Pro	missense_variant	Exon 2 of 8		NP_001317956.2
HADH	XR_007096395.1	n.301T>C		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8	c.257T>C	p.Leu86Pro	missense_variant	Exon 2 of 8	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131686 AN: 151928 Hom.: 57953 Cov.: 29

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.931

Gnomad ASJ AF: 0.975

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.902

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.893

GnomAD3 exomes AF: 0.921 AC: 231638 AN: 251446 Hom.: 107303 AF XY: 0.921 AC XY: 125166 AN XY: 135906

Gnomad AFR exome AF: 0.695

Gnomad AMR exome AF: 0.963

Gnomad ASJ exome AF: 0.975

Gnomad EAS exome AF: 0.975

Gnomad SAS exome AF: 0.896

Gnomad FIN exome AF: 0.961

Gnomad NFE exome AF: 0.926

Gnomad OTH exome AF: 0.931

GnomAD4 exome AF: 0.919 AC: 1338010 AN: 1455316 Hom.: 616459 Cov.: 34 AF XY: 0.919 AC XY: 665677 AN XY: 724400

Gnomad4 AFR exome AF: 0.694

Gnomad4 AMR exome AF: 0.959

Gnomad4 ASJ exome AF: 0.975

Gnomad4 EAS exome AF: 0.968

Gnomad4 SAS exome AF: 0.896

Gnomad4 FIN exome AF: 0.960

Gnomad4 NFE exome AF: 0.921

Gnomad4 OTH exome AF: 0.919

GnomAD4 genome AF: 0.867 AC: 131787 AN: 152048 Hom.: 57994 Cov.: 29 AF XY: 0.871 AC XY: 64705 AN XY: 74320

Gnomad4 AFR AF: 0.697

Gnomad4 AMR AF: 0.931

Gnomad4 ASJ AF: 0.975

Gnomad4 EAS AF: 0.972

Gnomad4 SAS AF: 0.902

Gnomad4 FIN AF: 0.963

Gnomad4 NFE AF: 0.923

Gnomad4 OTH AF: 0.894

Alfa AF: 0.919 Hom.: 152185

Bravo AF: 0.859

TwinsUK AF: 0.916 AC: 3398

ALSPAC AF: 0.920 AC: 3546

ESP6500AA AF: 0.704 AC: 3104

ESP6500EA AF: 0.924 AC: 7944

ExAC AF: 0.915 AC: 111095

Asia WGS AF: 0.923 AC: 3211 AN: 3478

EpiCase AF: 0.926

EpiControl AF: 0.928

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 16, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.14
DEOGEN2	Benign	0.13	.;.;T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.12	T;T;T;T;T
MetaRNN	Benign	7.2e-7	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.0	.;N;N;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	5.9	.;.;N;N;.
REVEL	Benign	0.27
Sift	Benign	1.0	.;.;T;T;.
Sift4G	Benign	0.71	.;T;T;.;T
Polyphen		0.0	.;.;B;.;.
Vest4		0.050, 0.047, 0.074
MPC		0.38
ClinPred		0.0075	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.54

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: rs4956145; hg19: chr4-108931039;