X-155026993-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_023934.4(FUNDC2):c.55C>T(p.His19Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,201,835 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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: 0.000020 ( 0 hom. 9 hem. )

Consequence

FUNDC2
NM_023934.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.269

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hemophilia A
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
mild hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
moderately severe hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
severe hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of hemophilia A in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

F8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06577575).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023934.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUNDC2	NM_023934.4	MANE Select	c.55C>T	p.His19Tyr	missense	Exon 1 of 5	NP_076423.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUNDC2	ENST00000369498.8	TSL:1 MANE Select	c.55C>T	p.His19Tyr	missense	Exon 1 of 5	ENSP00000358510.3	Q9BWH2
FUNDC2	ENST00000856523.1		c.55C>T	p.His19Tyr	missense	Exon 3 of 7	ENSP00000526582.1
FUNDC2	ENST00000942567.1		c.55C>T	p.His19Tyr	missense	Exon 2 of 6	ENSP00000612626.1

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

159624

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000288

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000202

AC:

AN:

1089715

Hom.:

Cov.:

AF XY:

0.0000252

AC XY:

AN XY:

357173

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26235

American (AMR)

AF:

0.00

AC:

AN:

34717

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19209

East Asian (EAS)

AF:

0.00

AC:

AN:

29876

South Asian (SAS)

AF:

0.00

AC:

AN:

53030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4041

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

838678

Other (OTH)

AF:

0.00

AC:

AN:

45745

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30913

American (AMR)

AF:

0.00

AC:

AN:

10818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3509

South Asian (SAS)

AF:

0.00

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52940

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.95

CADD

Benign

7.3

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.025

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.066

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.27

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.0

REVEL

Benign

0.023

Sift

Benign

0.053

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.10

MVP

0.043

MPC

0.29

ClinPred

0.019

GERP RS

-0.77

PromoterAI

0.012

Neutral

(source)

Varity_R

0.059

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over