X-155026975-G-A

Position:

• chrX-155026975-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023934.4(FUNDC2):​c.37G>A​(p.Val13Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FUNDC2 NM_023934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.228

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]

ACMG classification

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=0.09125906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUNDC2	NM_023934.4	c.37G>A	p.Val13Met	missense_variant	1/5	ENST00000369498.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUNDC2	ENST00000369498.8	c.37G>A	p.Val13Met	missense_variant	1/5	1	NM_023934.4	P1
FUNDC2	ENST00000475165.5	n.242+295G>A		intron_variant, non_coding_transcript_variant		3
F8	ENST00000423959.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.37G>A (p.V13M) alteration is located in exon 1 (coding exon 1) of the FUNDC2 gene. This alteration results from a G to A substitution at nucleotide position 37, causing the valine (V) at amino acid position 13 to be replaced by a methionine (M). 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	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.97
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.023
Sift	Benign	0.030	D
Sift4G	Benign	0.090	T
Polyphen		0.021	B
Vest4		0.067
MutPred		0.24		Loss of sheet (P = 0.0054);
MVP		0.082
MPC		0.25
ClinPred		0.061	T
GERP RS		-6.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-154255250;