X-155027008-C-T

Variant names:

• chrX-155027008-C-T
• rs782418293
• NM_023934.4:c.70C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023934.4(FUNDC2):​c.70C>T​(p.Arg24Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,202,782 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 0 hem.)
• Consequence: FUNDC2 NM_023934.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101052076).

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.70C>T	p.Arg24Cys	missense	Exon 1 of 5	NP_076423.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUNDC2	ENST00000369498.8	TSL:1 MANE Select	c.70C>T	p.Arg24Cys	missense	Exon 1 of 5	ENSP00000358510.3	Q9BWH2
	FUNDC2	ENST00000856523.1		c.70C>T	p.Arg24Cys	missense	Exon 3 of 7	ENSP00000526582.1
	FUNDC2	ENST00000942567.1		c.70C>T	p.Arg24Cys	missense	Exon 2 of 6	ENSP00000612626.1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112118 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000285

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

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 161437 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1090664 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 357700

African (AFR) AF: 0.00 AC: 0 AN: 26215

American (AMR) AF: 0.00 AC: 0 AN: 34779

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19238

East Asian (EAS) AF: 0.000167 AC: 5 AN: 29905

South Asian (SAS) AF: 0.00 AC: 0 AN: 53185

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4041

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838847

Other (OTH) AF: 0.00 AC: 0 AN: 45786

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112118 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34284

African (AFR) AF: 0.00 AC: 0 AN: 30873

American (AMR) AF: 0.00 AC: 0 AN: 10817

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6169

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52947

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.41
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.085	T
Polyphen		0.99	D
Vest4		0.10
MutPred		0.30		Loss of MoRF binding (P = 0.0143)
MVP		0.043
MPC		0.33
ClinPred		0.13	T
GERP RS		0.96
PromoterAI		0.10	Neutral
Varity_R		0.14
gMVP		0.30
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs782418293; hg19: chrX-154255283;