9-21031586-C-A

Position:

• chr9-21031586-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010915.5(HACD4):​c.5G>T​(p.Gly2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000855 in 1,286,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: HACD4 NM_001010915.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.187

Genes affected

HACD4 (HGNC:20920): (3-hydroxyacyl-CoA dehydratase 4) Enables 3-hydroxyacyl-CoA dehydratase activity and enzyme binding activity. Involved in fatty acid elongation and very long-chain fatty acid biosynthetic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10892576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HACD4	NM_001010915.5	c.5G>T	p.Gly2Val	missense_variant	1/7	ENST00000495827.3	NP_001010915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HACD4	ENST00000495827.3	c.5G>T	p.Gly2Val	missense_variant	1/7	2	NM_001010915.5	ENSP00000419503.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000855 AC: 11 AN: 1286320 Hom.: 0 Cov.: 34 AF XY: 0.0000142 AC XY: 9 AN XY: 631902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000106

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.5G>T (p.G2V) alteration is located in exon 1 (coding exon 1) of the HACD4 gene. This alteration results from a G to T substitution at nucleotide position 5, causing the glycine (G) at amino acid position 2 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.033
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.14
MutPred		0.30		Loss of disorder (P = 0.0227);
MVP		0.24
MPC		0.28
ClinPred		0.46	T
GERP RS		1.1
Varity_R		0.17
gMVP		0.59

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: rs1232762991; hg19: chr9-21031585;