3-123584970-C-G

Variant names:

• chr3-123584970-C-G
• rs770404869
• NM_198402.5:c.58G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198402.5(HACD2):​c.58G>C​(p.Ala20Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,334,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. A20S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: HACD2 NM_198402.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.927
• 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]

MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11908594).

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.58G>C	p.Ala20Pro	missense	Exon 1 of 7	NP_940684.1	Q6Y1H2
	HACD2	NM_001329783.2		c.58G>C	p.Ala20Pro	missense	Exon 1 of 8	NP_001316712.1
	HACD2	NM_001329784.4		c.-413G>C		5_prime_UTR	Exon 1 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.58G>C	p.Ala20Pro	missense	Exon 1 of 7	ENSP00000373153.5	Q6Y1H2
	HACD2	ENST00000865300.1		c.58G>C	p.Ala20Pro	missense	Exon 1 of 7	ENSP00000535359.1
	HACD2	ENST00000865299.1		c.58G>C	p.Ala20Pro	missense	Exon 1 of 5	ENSP00000535358.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 119438 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 20 AN: 1334132 Hom.: 0 Cov.: 32 AF XY: 0.0000182 AC XY: 12 AN XY: 658012

African (AFR) AF: 0.00 AC: 0 AN: 28130

American (AMR) AF: 0.0000303 AC: 1 AN: 33052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22468

East Asian (EAS) AF: 0.00 AC: 0 AN: 31198

South Asian (SAS) AF: 0.00 AC: 0 AN: 76898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4904

European-Non Finnish (NFE) AF: 0.0000182 AC: 19 AN: 1042524

Other (OTH) AF: 0.00 AC: 0 AN: 54160

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.93
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.034
Sift	Benign	0.083	T
Sift4G	Benign	0.13	T
Polyphen		0.028	B
Vest4		0.22
MutPred		0.29		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.068
MPC		0.85
ClinPred		0.20	T
GERP RS		0.38
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.63
Mutation Taster		=85/15	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: rs770404869; hg19: chr3-123303817;