20-3146796-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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
• Publications: 0 publications found

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

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=0.2189984).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021826.5. 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
	FASTKD5	NM_021826.5	MANE Select	c.2275G>A	p.Val759Ile	missense	Exon 2 of 2	NP_068598.1	Q7L8L6
	UBOX5	NM_014948.4	MANE Select	c.-42+12970G>A		intron	N/A	NP_055763.1	O94941-1
	UBOX5	NM_001267584.2		c.-42+12970G>A		intron	N/A	NP_001254513.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD5	ENST00000380266.4	TSL:1 MANE Select	c.2275G>A	p.Val759Ile	missense	Exon 2 of 2	ENSP00000369618.3	Q7L8L6
	UBOX5	ENST00000217173.7	TSL:1 MANE Select	c.-42+12970G>A		intron	N/A	ENSP00000217173.2	O94941-1
	UBOX5	ENST00000348031.6	TSL:1	c.-42+12970G>A		intron	N/A	ENSP00000311726.3	O94941-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.2
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
Mutation Taster		=94/6	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

hg19: chr20-3127442;