Genetic Variant NM_138378.3:c.73G>C (chr11-111879060-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138378.3(FDXACB1):c.73G>C(p.Asp25His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,552 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: 0.0000055 ( 0 hom. )

Consequence

FDXACB1
NM_138378.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

FDXACB1 (HGNC:25110): (ferredoxin-fold anticodon binding domain containing 1) This gene encodes a protein which contains a ferredoxin-fold anticodon-binding domain which is contained in a subset of phenylalanyl tRNA synthetases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

FDXACB1 links:

ENSG00000258529 (HGNC:):

ENSG00000258529 links:

CFAP68 (HGNC:1163): (cilia and flagella associated protein 68) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CFAP68 links:

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ACMG classification

Classification made for transcript

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=0.16542593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDXACB1	NM_138378.3 link	c.73G>C	p.Asp25His	missense_variant	Exon 1 of 5	ENST00000260257.9	NP_612387.1	Q9BRP7-1
FDXACB1	NR_038364.2 link	n.106G>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDXACB1	ENST00000260257.9 link	c.73G>C	p.Asp25His	missense_variant	Exon 1 of 5	1	NM_138378.3	ENSP00000260257.4		Q9BRP7-1
ENSG00000258529	ENST00000622211.4 link	c.73G>C	p.Asp25His	missense_variant	Exon 1 of 19	2		ENSP00000482396.1		A0A087WZ62

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461552

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73G>C (p.D25H) alteration is located in exon 1 (coding exon 1) of the FDXACB1 gene. This alteration results from a G to C substitution at nucleotide position 73, causing the aspartic acid (D) at amino acid position 25 to be replaced by a histidine (H). 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

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0039

.;T

Eigen

Benign

0.0068

Eigen_PC

Benign

-0.0037

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.60

.;N

REVEL

Benign

0.13

Sift

Benign

0.24

.;T

Sift4G

Uncertain

0.014

D;T

Polyphen

0.98

.;D

Vest4

0.21

MutPred

0.40

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.23

MPC

0.30

ClinPred

0.42

GERP RS

6.2

Varity_R

0.33

gMVP

0.41

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