Variant chr9-21007059-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010915.5(HACD4):c.677C>G(p.Pro226Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,428,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

HACD4
NM_001010915.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028395325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HACD4	NM_001010915.5 linkuse as main transcript	c.677C>G	p.Pro226Arg	missense_variant	7/7	ENST00000495827.3	NP_001010915.2	Q5VWC8
HACD4	NM_001321903.2 linkuse as main transcript	c.830C>G	p.Pro277Arg	missense_variant	9/9		NP_001308832.1
HACD4	NM_001321883.2 linkuse as main transcript	c.566C>G	p.Pro189Arg	missense_variant	7/7		NP_001308812.1	Q5VWC8
HACD4	XM_017014713.2 linkuse as main transcript	c.719C>G	p.Pro240Arg	missense_variant	9/9		XP_016870202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HACD4	ENST00000495827.3 linkuse as main transcript	c.677C>G	p.Pro226Arg	missense_variant	7/7	2	NM_001010915.5	ENSP00000419503.1		Q5VWC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000843

AC:

AN:

249040

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1428476

Hom.:

Cov.:

AF XY:

0.0000491

AC XY:

AN XY:

712804

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000409

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000555

Gnomad4 OTH exome

AF:

0.0000844

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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

Feb 06, 2024

The c.677C>G (p.P226R) alteration is located in exon 7 (coding exon 7) of the HACD4 gene. This alteration results from a C to G substitution at nucleotide position 677, causing the proline (P) at amino acid position 226 to be replaced by an arginine (R). 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

0.091

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

DANN

Benign

0.81

DEOGEN2

Benign

0.0054

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.70

M_CAP

Benign

0.0033

MetaRNN

Benign

0.028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.33

PROVEAN

Benign

0.82

REVEL

Benign

0.033

Sift

Benign

0.76

Sift4G

Benign

0.60

Polyphen

0.037

Vest4

0.13

MutPred

0.43

Gain of MoRF binding (P = 2e-04);

MVP

0.31

MPC

0.038

ClinPred

0.035

GERP RS

4.6

Varity_R

0.056

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over