1-247857254-G-C

Variant names:

• chr1-247857254-G-C
• rs11204523
• NM_015431.4:c.8G>C

Variant summary

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

The NM_015431.4(TRIM58):​c.8G>C​(p.Trp3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,322,986 control chromosomes in the GnomAD database, including 363,990 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.67 (35530 hom., cov: 35)
  • Exomes 𝑓: 0.75 (328460 hom.)
• Consequence: TRIM58 NM_015431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.819
• Publications: 22 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=1.5333981E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM58	NM_015431.4	MANE Select	c.8G>C	p.Trp3Ser	missense	Exon 1 of 6	NP_056246.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM58	ENST00000366481.4	TSL:1 MANE Select	c.8G>C	p.Trp3Ser	missense	Exon 1 of 6	ENSP00000355437.3

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101701 AN: 152022 Hom.: 35511 Cov.: 35

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.701

GnomAD2 exomes AF: 0.736 AC: 18478 AN: 25098 AF XY: 0.739

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.719

Gnomad ASJ exome AF: 0.777

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.761

Gnomad NFE exome AF: 0.754

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.747 AC: 874597 AN: 1170856 Hom.: 328460 Cov.: 67 AF XY: 0.748 AC XY: 420747 AN XY: 562610

African (AFR) AF: 0.425 AC: 10249 AN: 24106

American (AMR) AF: 0.735 AC: 7610 AN: 10354

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 12535 AN: 15714

East Asian (EAS) AF: 0.751 AC: 20389 AN: 27154

South Asian (SAS) AF: 0.753 AC: 30987 AN: 41134

European-Finnish (FIN) AF: 0.768 AC: 31392 AN: 40878

Middle Eastern (MID) AF: 0.762 AC: 2803 AN: 3678

European-Non Finnish (NFE) AF: 0.753 AC: 723830 AN: 960798

Other (OTH) AF: 0.740 AC: 34802 AN: 47040

GnomAD4 genome AF: 0.669 AC: 101752 AN: 152130 Hom.: 35530 Cov.: 35 AF XY: 0.671 AC XY: 49889 AN XY: 74348

African (AFR) AF: 0.449 AC: 18659 AN: 41514

American (AMR) AF: 0.720 AC: 11015 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2773 AN: 3470

East Asian (EAS) AF: 0.775 AC: 3974 AN: 5126

South Asian (SAS) AF: 0.764 AC: 3686 AN: 4822

European-Finnish (FIN) AF: 0.769 AC: 8154 AN: 10602

Middle Eastern (MID) AF: 0.699 AC: 204 AN: 292

European-Non Finnish (NFE) AF: 0.752 AC: 51133 AN: 67984

Other (OTH) AF: 0.702 AC: 1485 AN: 2116

Alfa AF: 0.606 Hom.: 1845

Bravo AF: 0.657

TwinsUK AF: 0.754 AC: 2797

ALSPAC AF: 0.743 AC: 2863

ESP6500AA AF: 0.507 AC: 2027

ESP6500EA AF: 0.766 AC: 5979

ExAC AF: 0.640 AC: 54439

Asia WGS AF: 0.786 AC: 2731 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.5
DANN	Benign	0.52
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.8	N
PhyloP100		0.82
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	4.1	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		1.4
ClinPred		0.0071	T
GERP RS		3.0
PromoterAI		0.0096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.097
gMVP		0.14
Mutation Taster		=100/0	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: rs11204523; hg19: chr1-248020556; COSMIC: COSV63569287;