1-247864729-C-G

Variant names:

• chr1-247864729-C-G
• rs368652011
• NM_015431.4:c.541C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015431.4(TRIM58):​c.541C>G​(p.Arg181Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIM58 NM_015431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127
• Publications: 0 publications found

Genes affected

TRIM58 (HGNC:24150): (tripartite motif containing 58) Predicted to enable dynein heavy chain binding activity; dynein intermediate chain binding activity; and ubiquitin protein ligase activity. Predicted to be involved in several processes, including positive regulation of erythrocyte enucleation; protein ubiquitination; and regulation of nuclear migration along microtubule. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015431.4. 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
	TRIM58	NM_015431.4	MANE Select	c.541C>G	p.Arg181Gly	missense	Exon 3 of 6	NP_056246.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM58	ENST00000366481.4	TSL:1 MANE Select	c.541C>G	p.Arg181Gly	missense	Exon 3 of 6	ENSP00000355437.3	Q8NG06

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.13
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.076
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.046	D
Polyphen		0.058	B
Vest4		0.48
MutPred		0.38		Loss of MoRF binding (P = 0.0884)
MVP		0.28
MPC		0.18
ClinPred		0.71	D
GERP RS		1.2
Varity_R		0.13
gMVP		0.23
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368652011; hg19: chr1-248028031;