20-3146796-C-T

Variant names:

• chr20-3146796-C-T
• NM_021826.5:c.2275G>A

Variant summary

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

The NM_021826.5(FASTKD5):​c.2275G>A​(p.Val759Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V759A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FASTKD5 NM_021826.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

FASTKD5 (HGNC:25790): (FAST kinase domains 5) Enables rRNA binding activity. Involved in mitochondrial RNA processing. Located in mitochondrial nucleoid and ribonucleoprotein granule. [provided by Alliance of Genome Resources, Apr 2022]

UBOX5 (HGNC:17777): (U-box domain containing 5) This gene encodes a U-box domain containing protein. The encoded protein interacts with E2 enzymes and may play a role in the ubiquitination pathway. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

UBOX5-AS1 (HGNC:44111): (UBOX5 antisense RNA 1)

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=0.2189984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASTKD5	NM_021826.5	c.2275G>A	p.Val759Ile	missense_variant	Exon 2 of 2	ENST00000380266.4	NP_068598.1
UBOX5	NM_014948.4	c.-42+12970G>A		intron_variant	Intron 1 of 4	ENST00000217173.7	NP_055763.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASTKD5	ENST00000380266.4	c.2275G>A	p.Val759Ile	missense_variant	Exon 2 of 2	1	NM_021826.5	ENSP00000369618.3
UBOX5	ENST00000217173.7	c.-42+12970G>A		intron_variant	Intron 1 of 4	1	NM_014948.4	ENSP00000217173.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2275G>A (p.V759I) alteration is located in exon 2 (coding exon 1) of the FASTKD5 gene. This alteration results from a G to A substitution at nucleotide position 2275, causing the valine (V) at amino acid position 759 to be replaced by an isoleucine (I). 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	0.089
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.63	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.067
Sift	Benign	0.59	T
Sift4G	Benign	0.20	T
Polyphen		0.82	P
Vest4		0.39
MutPred		0.37		Loss of methylation at K758 (P = 0.0648);
MVP		0.12
MPC		0.098
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.067
gMVP		0.11

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: chr20-3127442;