Genetic Variant TRIB1:p.Pro62Ala (chr8-125431086-C-G) – 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_025195.4(TRIB1):c.184C>G(p.Pro62Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00009 in 1,389,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P62S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

TRIB1
NM_025195.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.525

Publications

2 publications found

Variant links:

Genes affected

TRIB1 (HGNC:16891): (tribbles pseudokinase 1) Enables mitogen-activated protein kinase kinase binding activity and protein kinase inhibitor activity. Involved in several processes, including JNK cascade; negative regulation of lipopolysaccharide-mediated signaling pathway; and regulation of protein kinase activity. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TRIB1 links:

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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=0.0044450164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025195.4. 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
	TRIB1	NM_025195.4	MANE Select	c.184C>G	p.Pro62Ala	missense	Exon 1 of 3	NP_079471.1	Q96RU8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIB1	ENST00000311922.4	TSL:1 MANE Select	c.184C>G	p.Pro62Ala	missense	Exon 1 of 3	ENSP00000312150.3	Q96RU8-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000445

AC:

AN:

20220

AF XY:

0.000401

show subpopulations

Gnomad AFR exome

AF:

0.00568

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00295

Gnomad NFE exome

AF:

0.000146

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000590

AC:

AN:

1237264

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

605444

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

24376

American (AMR)

AF:

0.0000711

AC:

AN:

14068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18600

East Asian (EAS)

AF:

0.00

AC:

AN:

27404

South Asian (SAS)

AF:

0.00

AC:

AN:

57852

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

30736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3562

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

1009838

Other (OTH)

AF:

0.0000787

AC:

AN:

50828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000342

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41518

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

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:

0.000159

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.000114

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.13

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.55

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

PhyloP100

0.53

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.45

REVEL

Benign

0.041

Sift

Benign

0.11

Sift4G

Benign

0.17

Polyphen

0.018

Vest4

0.15

MutPred

0.18

Loss of glycosylation at P62 (P = 0.0253)

MVP

0.32

MPC

0.44

ClinPred

0.0079

GERP RS

1.6

Varity_R

0.069

gMVP

0.27

Mutation Taster

=92/8

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