4-108009883-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005327.7(HADH):​c.257T>G​(p.Leu86Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L86P) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
• Consequence: HADH NM_005327.7 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 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.257T>G	p.Leu86Arg	missense_variant	Exon 2 of 8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4	c.257T>G	p.Leu86Arg	missense_variant	Exon 2 of 9		NP_001171634.3
HADH	NM_001331027.2	c.269T>G	p.Leu90Arg	missense_variant	Exon 2 of 8		NP_001317956.2
HADH	XR_007096395.1	n.301T>G		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>G	p.Leu86Arg	missense_variant	Exon 2 of 8	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74208

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	0.0076	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	.;.;T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.050	.;N;N;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.74	.;.;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.042	.;.;D;D;.
Sift4G	Benign	0.47	.;T;T;.;T
Polyphen		0.0020	.;.;B;.;.
Vest4		0.21, 0.18, 0.19
MutPred		0.45		.;.;.;.;Gain of solvent accessibility (P = 0.0018);
MVP		0.78
MPC		0.38
ClinPred		0.79	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -1

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;