X-155026961-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_023934.4(FUNDC2):c.23C>A(p.Ala8Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000056 in 1,197,422 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000061 ( 0 hom. 26 hem. )

Consequence

FUNDC2
NM_023934.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.04

Variant links:

Genes affected

FUNDC2 (HGNC:24925): (FUN14 domain containing 2) Predicted to be involved in autophagy of mitochondrion. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

FUNDC2 links:

F8 (HGNC:3546): (coagulation factor VIII) This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]

F8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16776323).

BS2

High Hemizygotes in GnomAdExome4 at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUNDC2	NM_023934.4 link	c.23C>A	p.Ala8Asp	missense_variant	Exon 1 of 5	ENST00000369498.8	NP_076423.2	Q9BWH2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUNDC2	ENST00000369498.8 link	c.23C>A	p.Ala8Asp	missense_variant	Exon 1 of 5	1	NM_023934.4	ENSP00000358510.3		Q9BWH2

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112173

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34349

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

152880

Hom.:

AF XY:

0.0000211

AC XY:

AN XY:

47408

show subpopulations

Gnomad AFR exome

AF:

0.0000956

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:

0.0000603

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000608

AC:

AN:

1085249

Hom.:

Cov.:

AF XY:

0.0000733

AC XY:

AN XY:

354839

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:

0.0000776

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112173

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34349

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>A (p.A8D) alteration is located in exon 1 (coding exon 1) of the FUNDC2 gene. This alteration results from a C to A substitution at nucleotide position 23, causing the alanine (A) at amino acid position 8 to be replaced by an aspartic acid (D). 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

0.15

BayesDel_addAF

Benign

-0.00018

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.68

REVEL

Benign

0.10

Sift

Uncertain

0.0020

Sift4G

Benign

0.092

Polyphen

0.62

Vest4

0.43

MutPred

0.11

Loss of MoRF binding (P = 0.018);

MVP

0.093

MPC

0.55

ClinPred

0.15

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.49

gMVP

0.31

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