chr3-123567768-C-A

Variant names:

• chr3-123567768-C-A
• rs769409686
• NM_198402.5:c.286G>T

Variant summary

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

The NM_198402.5(HACD2):​c.286G>T​(p.Ala96Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,498,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: HACD2 NM_198402.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• 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.286G>T	p.Ala96Ser	missense	Exon 3 of 7	NP_940684.1	Q6Y1H2
	HACD2	NM_001329783.2		c.355G>T	p.Ala119Ser	missense	Exon 4 of 8	NP_001316712.1
	HACD2	NM_001329784.4		c.-185G>T		5_prime_UTR	Exon 3 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.286G>T	p.Ala96Ser	missense	Exon 3 of 7	ENSP00000373153.5	Q6Y1H2
	HACD2	ENST00000865300.1		c.286G>T	p.Ala96Ser	missense	Exon 3 of 7	ENSP00000535359.1
	HACD2	ENST00000469317.1	TSL:3	c.-10G>T		5_prime_UTR	Exon 3 of 6	ENSP00000419237.1	C9JWG1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000154 AC: 3 AN: 194312 AF XY: 0.0000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000312

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000327 AC: 44 AN: 1346888 Hom.: 0 Cov.: 24 AF XY: 0.0000432 AC XY: 29 AN XY: 671844

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28626

American (AMR) AF: 0.00 AC: 0 AN: 29476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23188

East Asian (EAS) AF: 0.00 AC: 0 AN: 35822

South Asian (SAS) AF: 0.00 AC: 0 AN: 71270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5392

European-Non Finnish (NFE) AF: 0.0000411 AC: 43 AN: 1046058

Other (OTH) AF: 0.0000180 AC: 1 AN: 55590

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000722633), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000908 Hom.: 0

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.057	T
Sift4G	Benign	0.085	T
Polyphen		0.80	P
Vest4		0.61
MutPred		0.67		Gain of sheet (P = 0.1208)
MVP		0.18
MPC		1.2
ClinPred		0.58	D
GERP RS		4.6
Varity_R		0.21
gMVP		0.56
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs769409686; hg19: chr3-123286615;