20-3147001-C-T

Variant names:

• chr20-3147001-C-T
• rs1331570689
• NM_021826.5:c.2070G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021826.5(FASTKD5):​c.2070G>A​(p.Met690Ile) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FASTKD5 NM_021826.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0520

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053859174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASTKD5	NM_021826.5	c.2070G>A	p.Met690Ile	missense_variant	Exon 2 of 2	ENST00000380266.4	NP_068598.1
UBOX5	NM_014948.4	c.-42+12765G>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.2070G>A	p.Met690Ile	missense_variant	Exon 2 of 2	1	NM_021826.5	ENSP00000369618.3
UBOX5	ENST00000217173.7	c.-42+12765G>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

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2070G>A (p.M690I) 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 2070, causing the methionine (M) at amino acid position 690 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	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.5
DANN	Benign	0.54
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.025
Sift	Benign	0.43	T
Sift4G	Benign	0.50	T
Polyphen		0.0030	B
Vest4		0.062
MutPred		0.44		Loss of loop (P = 0.0112);
MVP		0.13
MPC		0.079
ClinPred		0.041	T
GERP RS		2.0
Varity_R		0.044
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

LitVar

Other links and lift over

dbSNP: rs1331570689; hg19: chr20-3127647;