Genetic Variant NM_020358.2:c.1085G>A (chr11-89798404-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020358.2(TRIM49):c.1085G>A(p.Arg362Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000518 in 1,603,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TRIM49
NM_020358.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.218

Publications

4 publications found

Variant links:

Genes affected

TRIM49 (HGNC:13431): (tripartite motif containing 49) The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. This gene has been found to be preferentially expressed in testis. Related pseudogenes and gene duplicates have also been identified on chromosome 11. [provided by RefSeq, Aug 2010]

TRIM49 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014789134).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020358.2. 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
	TRIM49	NM_020358.2	MANE Select	c.1085G>A	p.Arg362Gln	missense	Exon 8 of 8	NP_065091.1	P0CI25

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM49	ENST00000329758.5	TSL:1 MANE Select	c.1085G>A	p.Arg362Gln	missense	Exon 8 of 8	ENSP00000327604.1	P0CI25
	TRIM49	ENST00000532501.2	TSL:5	c.854G>A	p.Arg285Gln	missense	Exon 6 of 6	ENSP00000431618.2	E9PK69

Frequencies

GnomAD3 genomes

AF:

0.000160

AC:

AN:

143610

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000543

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000293

Gnomad EAS

AF:

0.000214

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

250900

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.000684

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1459368

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726040

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

33088

American (AMR)

AF:

0.0000224

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26104

East Asian (EAS)

AF:

0.000563

AC:

AN:

39060

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1111040

Other (OTH)

AF:

0.0000996

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000174

AC:

AN:

143714

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

AN XY:

69976

show subpopulations

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

African (AFR)

AF:

0.000596

AC:

AN:

36908

American (AMR)

AF:

0.00

AC:

AN:

14294

Ashkenazi Jewish (ASJ)

AF:

0.000293

AC:

AN:

3418

East Asian (EAS)

AF:

0.000215

AC:

AN:

4658

South Asian (SAS)

AF:

0.00

AC:

AN:

4630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66746

Other (OTH)

AF:

0.00

AC:

AN:

2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000128441), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.390

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000288

Hom.:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0040

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.60

M_CAP

Benign

0.0063

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.88

PhyloP100

0.22

PrimateAI

Benign

0.32

PROVEAN

Benign

0.32

REVEL

Benign

0.013

Sift

Benign

0.54

Sift4G

Benign

0.32

Polyphen

0.012

Vest4

0.13

MVP

0.043

MPC

1.5

ClinPred

0.0091

GERP RS

-0.11

Varity_R

0.043

gMVP

0.036

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over