5-154820444-C-T

Variant names:

• chr5-154820444-C-T
• rs748448192
• NM_032385.5:c.874G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032385.5(FAXDC2):​c.874G>A​(p.Val292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000027 (0 hom.)
• Consequence: FAXDC2 NM_032385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

FAXDC2 (HGNC:1334): (fatty acid hydroxylase domain containing 2) Predicted to enable C-4 methylsterol oxidase activity. Involved in positive regulation of megakaryocyte differentiation and positive regulation of protein phosphorylation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.38073486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAXDC2	NM_032385.5	c.874G>A	p.Val292Met	missense_variant	Exon 9 of 9	ENST00000326080.10	NP_115761.2
FAXDC2	XM_006714753.3	c.874G>A	p.Val292Met	missense_variant	Exon 10 of 10		XP_006714816.1
FAXDC2	XM_047416652.1	c.454G>A	p.Val152Met	missense_variant	Exon 6 of 6		XP_047272608.1
FAXDC2	XM_047416654.1	c.454G>A	p.Val152Met	missense_variant	Exon 5 of 5		XP_047272610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAXDC2	ENST00000326080.10	c.874G>A	p.Val292Met	missense_variant	Exon 9 of 9	1	NM_032385.5	ENSP00000320604.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460942 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726774

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.874G>A (p.V292M) alteration is located in exon 9 (coding exon 8) of the FAXDC2 gene. This alteration results from a G to A substitution at nucleotide position 874, causing the valine (V) at amino acid position 292 to be replaced by a methionine (M). 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	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.93	P;.
Vest4		0.19
MutPred		0.57		Loss of catalytic residue at V292 (P = 0.0045);.;
MVP		0.35
MPC		0.36
ClinPred		0.96	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.73

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: rs748448192; hg19: chr5-154200004;