3-123582256-T-A

Variant names:

• chr3-123582256-T-A
• rs760203086
• NM_198402.5:c.229A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198402.5(HACD2):​c.229A>T​(p.Ile77Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,738 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I77V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HACD2 NM_198402.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.72
• Publications: 0 publications found

Genes affected

HACD2 (HGNC:9640): (3-hydroxyacyl-CoA dehydratase 2) The protein encoded by this gene can catalyze the third step (dehydration) in the conversion of long chain fatty acids to very long chain fatty acids. The encoded protein localizes to the endoplasmic reticulum membrane. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198402.5. 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
	HACD2	NM_198402.5	MANE Select	c.229A>T	p.Ile77Phe	missense	Exon 2 of 7	NP_940684.1	Q6Y1H2
	HACD2	NM_001329783.2		c.229A>T	p.Ile77Phe	missense	Exon 2 of 8	NP_001316712.1
	HACD2	NM_001329784.4		c.-242A>T		5_prime_UTR	Exon 2 of 9	NP_001316713.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACD2	ENST00000383657.10	TSL:1 MANE Select	c.229A>T	p.Ile77Phe	missense	Exon 2 of 7	ENSP00000373153.5	Q6Y1H2
	HACD2	ENST00000865300.1		c.229A>T	p.Ile77Phe	missense	Exon 2 of 7	ENSP00000535359.1
	HACD2	ENST00000865299.1		c.229A>T	p.Ile77Phe	missense	Exon 2 of 5	ENSP00000535358.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245070 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455738 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724208

African (AFR) AF: 0.00 AC: 0 AN: 33154

American (AMR) AF: 0.00 AC: 0 AN: 43922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39360

South Asian (SAS) AF: 0.00 AC: 0 AN: 85128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109100

Other (OTH) AF: 0.00 AC: 0 AN: 60082

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Benign	0.042	D
Sift4G	Benign	0.093	T
Polyphen		0.026	B
Vest4		0.79
MutPred		0.54		Loss of catalytic residue at I77 (P = 0.1933)
MVP		0.48
MPC		1.7
ClinPred		0.92	D
GERP RS		4.6
Varity_R		0.39
gMVP		0.90
Mutation Taster		=61/39	polymorphism

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: rs760203086; hg19: chr3-123301103;