1-247857271-C-T

Variant names:

• chr1-247857271-C-T
• rs758862161
• NM_015431.4:c.25C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015431.4(TRIM58):​c.25C>T​(p.Arg9Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,350,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: TRIM58 NM_015431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.405
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059432626).

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.25C>T	p.Arg9Trp	missense	Exon 1 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.25C>T	p.Arg9Trp	missense	Exon 1 of 6	ENSP00000355437.3	Q8NG06

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000259 AC: 1 AN: 38604 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1197954 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 578010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24620

American (AMR) AF: 0.00 AC: 0 AN: 11706

Ashkenazi Jewish (ASJ) AF: 0.0000615 AC: 1 AN: 16266

East Asian (EAS) AF: 0.00 AC: 0 AN: 27758

South Asian (SAS) AF: 0.00 AC: 0 AN: 46730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4014

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 975820

Other (OTH) AF: 0.00 AC: 0 AN: 48298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000898 AC: 1

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	Uncertain	0.34
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.41
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.13
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.41		Loss of disorder (P = 0.002)
MVP		0.63
MPC		0.94
ClinPred		0.51	D
GERP RS		2.5
PromoterAI		0.086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.18
gMVP		0.28
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

dbSNP: rs758862161; hg19: chr1-248020573; COSMIC: COSV100825119;