chr9-21026669-G-A

Position:

• chr9-21026669-G-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.197C>T​(p.Ser66Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: HACD4 NM_001010915.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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]

HACD4 (HGNC:):

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=0.2611922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HACD4	NM_001010915.5	c.197C>T	p.Ser66Phe	missense_variant	3/7	ENST00000495827.3	NP_001010915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HACD4	ENST00000495827.3	c.197C>T	p.Ser66Phe	missense_variant	3/7	2	NM_001010915.5	ENSP00000419503.1
HACD4	ENST00000488436.1	n.77C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135342

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

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

May 25, 2022

The c.197C>T (p.S66F) alteration is located in exon 3 (coding exon 3) of the HACD4 gene. This alteration results from a C to T substitution at nucleotide position 197, causing the serine (S) at amino acid position 66 to be replaced by a phenylalanine (F). 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	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.24
Sift	Benign	0.11	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.50
MutPred		0.73		Loss of methylation at R62 (P = 0.2116);
MVP		0.38
MPC		0.036
ClinPred		0.13	T
GERP RS		5.7
Varity_R		0.069
gMVP		0.65

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: rs765057497; hg19: chr9-21026668;