rs1339847

Variant names:

• chr1-247875992-G-A
• rs1339847
• NM_015431.4:c.964G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015431.4(TRIM58):​c.964G>A​(p.Val322Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,614,126 control chromosomes in the GnomAD database, including 10,452 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (914 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9538 hom.)
• Consequence: TRIM58 NM_015431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• Publications: 27 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018129051).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM58	NM_015431.4	c.964G>A	p.Val322Ile	missense_variant	Exon 6 of 6	ENST00000366481.4	NP_056246.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM58	ENST00000366481.4	c.964G>A	p.Val322Ile	missense_variant	Exon 6 of 6	1	NM_015431.4	ENSP00000355437.3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16096 AN: 152134 Hom.: 909 Cov.: 32

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.123 AC: 30979 AN: 251426 AF XY: 0.120

Gnomad AFR exome AF: 0.0793

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.111 AC: 162455 AN: 1461874 Hom.: 9538 Cov.: 31 AF XY: 0.111 AC XY: 80619 AN XY: 727242

African (AFR) AF: 0.0763 AC: 2556 AN: 33480

American (AMR) AF: 0.208 AC: 9299 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2949 AN: 26136

East Asian (EAS) AF: 0.151 AC: 5975 AN: 39696

South Asian (SAS) AF: 0.126 AC: 10875 AN: 86258

European-Finnish (FIN) AF: 0.102 AC: 5428 AN: 53418

Middle Eastern (MID) AF: 0.0742 AC: 428 AN: 5766

European-Non Finnish (NFE) AF: 0.107 AC: 118463 AN: 1112002

Other (OTH) AF: 0.107 AC: 6482 AN: 60396

GnomAD4 genome AF: 0.106 AC: 16109 AN: 152252 Hom.: 914 Cov.: 32 AF XY: 0.107 AC XY: 7955 AN XY: 74450

African (AFR) AF: 0.0817 AC: 3397 AN: 41558

American (AMR) AF: 0.155 AC: 2367 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 409 AN: 3468

East Asian (EAS) AF: 0.143 AC: 741 AN: 5182

South Asian (SAS) AF: 0.136 AC: 654 AN: 4816

European-Finnish (FIN) AF: 0.103 AC: 1091 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7081 AN: 68002

Other (OTH) AF: 0.102 AC: 216 AN: 2114

Alfa AF: 0.105 Hom.: 3550

Bravo AF: 0.111

TwinsUK AF: 0.106 AC: 392

ALSPAC AF: 0.109 AC: 421

ESP6500AA AF: 0.0824 AC: 363

ESP6500EA AF: 0.103 AC: 883

ExAC AF: 0.118 AC: 14390

Asia WGS AF: 0.128 AC: 444 AN: 3478

EpiCase AF: 0.0936

EpiControl AF: 0.0997

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.24
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.031
Sift	Benign	0.22	T
Sift4G	Benign	0.22	T
Polyphen		0.13	B
Vest4		0.051
MPC		0.17
ClinPred		0.021	T
GERP RS		1.9
Varity_R		0.063
gMVP		0.18
Mutation Taster		=295/5	polymorphism (auto)

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: rs1339847; hg19: chr1-248039294; COSMIC: COSV107459127;