Variant 9-21008146-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001010915.5(HACD4):c.491C>G(p.Ala164Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000103 in 1,451,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

HACD4
NM_001010915.5 missense, splice_region

Scores

Splicing: ADA: 0.01276

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.73

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33765674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HACD4	NM_001010915.5 linkuse as main transcript	c.491C>G	p.Ala164Gly	missense_variant, splice_region_variant	6/7	ENST00000495827.3	NP_001010915.2	Q5VWC8
HACD4	NM_001321903.2 linkuse as main transcript	c.644C>G	p.Ala215Gly	missense_variant, splice_region_variant	8/9		NP_001308832.1
HACD4	NM_001321883.2 linkuse as main transcript	c.380C>G	p.Ala127Gly	missense_variant, splice_region_variant	6/7		NP_001308812.1	Q5VWC8
HACD4	XM_017014713.2 linkuse as main transcript	c.533C>G	p.Ala178Gly	missense_variant, splice_region_variant	8/9		XP_016870202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HACD4	ENST00000495827.3 linkuse as main transcript	c.491C>G	p.Ala164Gly	missense_variant, splice_region_variant	6/7	2	NM_001010915.5	ENSP00000419503.1		Q5VWC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1451910

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722168

show subpopulations

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:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.491C>G (p.A164G) alteration is located in exon 6 (coding exon 6) of the HACD4 gene. This alteration results from a C to G substitution at nucleotide position 491, causing the alanine (A) at amino acid position 164 to be replaced by a glycine (G). 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

0.10

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

Eigen

Benign

0.012

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

M_CAP

Benign

0.016

MetaRNN

Benign

0.34

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.32

REVEL

Benign

0.17

Sift

Benign

0.30

Sift4G

Benign

0.33

Polyphen

0.022

Vest4

0.52

MutPred

0.67

Loss of stability (P = 0.0339);

MVP

0.55

MPC

0.080

ClinPred

0.42

GERP RS

5.9

Varity_R

0.068

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.013

dbscSNV1_RF

Benign

0.088

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over