20-3147158-G-C

Variant names:

• chr20-3147158-G-C
• rs1373654441
• NM_021826.5:c.1913C>G

Variant summary

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

The NM_021826.5(FASTKD5):​c.1913C>G​(p.Ala638Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: FASTKD5 NM_021826.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.975

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=0.04215482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASTKD5	NM_021826.5	c.1913C>G	p.Ala638Gly	missense_variant	Exon 2 of 2	ENST00000380266.4	NP_068598.1
UBOX5	NM_014948.4	c.-42+12608C>G		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.1913C>G	p.Ala638Gly	missense_variant	Exon 2 of 2	1	NM_021826.5	ENSP00000369618.3
UBOX5	ENST00000217173.7	c.-42+12608C>G		intron_variant	Intron 1 of 4	1	NM_014948.4	ENSP00000217173.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1913C>G (p.A638G) alteration is located in exon 2 (coding exon 1) of the FASTKD5 gene. This alteration results from a C to G substitution at nucleotide position 1913, causing the alanine (A) at amino acid position 638 to be replaced by a glycine (G). 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	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.047
Sift	Benign	0.13	T
Sift4G	Benign	0.30	T
Polyphen		0.085	B
Vest4		0.043
MutPred		0.31		Gain of methylation at R639 (P = 0.0528);
MVP		0.23
MPC		0.083
ClinPred		0.081	T
GERP RS		3.8
Varity_R		0.062
gMVP		0.30

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: rs1373654441; hg19: chr20-3127804;