X-155026993-C-A

Variant names:

• chrX-155026993-C-A
• rs1455563669
• NM_023934.4:c.55C>A

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.55C>A​(p.His19Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,714 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. H19Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: FUNDC2 NM_023934.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269
• 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=0.07361466).

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>A	p.His19Asn	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.55C>A	p.His19Asn	missense	Exon 1 of 5	ENSP00000358510.3	Q9BWH2
	FUNDC2	ENST00000856523.1		c.55C>A	p.His19Asn	missense	Exon 3 of 7	ENSP00000526582.1
	FUNDC2	ENST00000942567.1		c.55C>A	p.His19Asn	missense	Exon 2 of 6	ENSP00000612626.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089714 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 1 AN XY: 357172

African (AFR) AF: 0.00 AC: 0 AN: 26235

American (AMR) AF: 0.00 AC: 0 AN: 34717

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19209

East Asian (EAS) AF: 0.00 AC: 0 AN: 29876

South Asian (SAS) AF: 0.00 AC: 0 AN: 53030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38184

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

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838677

Other (OTH) AF: 0.00 AC: 0 AN: 45745

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.1
DANN	Benign	0.77
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.27
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.044
Sift	Benign	0.038	D
Sift4G	Benign	0.49	T
Polyphen		0.0090	B
Vest4		0.20
MutPred		0.14		Gain of methylation at R18 (P = 0.0583)
MVP		0.10
MPC		0.28
ClinPred		0.036	T
GERP RS		-0.77
PromoterAI		-0.018	Neutral
Varity_R		0.073
gMVP		0.14
Mutation Taster		=100/0	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: rs1455563669; hg19: chrX-154255268;