Genetic Variant NM_001160372.4:c.3149G>A (chr8-139732109-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001160372.4(TRAPPC9):c.3149G>A(p.Arg1050Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,606,834 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1050W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 7 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3O:1

Conservation

PhyloP100: 2.54

Publications

1 publications found

Variant links:

Genes affected

TRAPPC9 (HGNC:30832): (trafficking protein particle complex subunit 9) This gene encodes a protein that likely plays a role in NF-kappa-B signaling. Mutations in this gene have been associated with autosomal-recessive cognitive disability. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

TRAPPC9 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 13
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
intellectual disability-obesity-brain malformations-facial dysmorphism syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TRAPPC9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01266858).

BP6

Variant 8-139732109-C-T is Benign according to our data. Variant chr8-139732109-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 362064.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000978 (149/152320) while in subpopulation NFE AF = 0.00184 (125/68026). AF 95% confidence interval is 0.00158. There are 2 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160372.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAPPC9	NM_001160372.4	MANE Select	c.3149G>A	p.Arg1050Gln	missense	Exon 22 of 23	NP_001153844.1	Q96Q05-1
TRAPPC9	NM_001374682.1		c.3170G>A	p.Arg1057Gln	missense	Exon 23 of 24	NP_001361611.1
TRAPPC9	NM_031466.8		c.3149G>A	p.Arg1050Gln	missense	Exon 22 of 23	NP_113654.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAPPC9	ENST00000438773.4	TSL:1 MANE Select	c.3149G>A	p.Arg1050Gln	missense	Exon 22 of 23	ENSP00000405060.3	Q96Q05-1
TRAPPC9	ENST00000520857.5	TSL:1	c.2678G>A	p.Arg893Gln	missense	Exon 20 of 21	ENSP00000430116.1	H0YBR0
TRAPPC9	ENST00000521667.5	TSL:1	n.1554G>A		non_coding_transcript_exon	Exon 11 of 12

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000860

AC:

201

AN:

233732

AF XY:

0.000859

show subpopulations

Gnomad AFR exome

AF:

0.000207

Gnomad AMR exome

AF:

0.0000901

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000519

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.00197

AC:

2859

AN:

1454514

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1335

AN XY:

722930

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33398

American (AMR)

AF:

0.0000682

AC:

AN:

43984

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25930

East Asian (EAS)

AF:

0.00

AC:

AN:

39432

South Asian (SAS)

AF:

0.00

AC:

AN:

84930

European-Finnish (FIN)

AF:

0.000115

AC:

AN:

52054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00252

AC:

2792

AN:

1109144

Other (OTH)

AF:

0.000866

AC:

AN:

60020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

169

338

506

675

844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.000978

AC:

149

AN:

152320

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41574

American (AMR)

AF:

0.000327

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00184

AC:

125

AN:

68026

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00141

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000819

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal recessive 13 (3)

not provided (2)

not specified (2)

Inborn genetic diseases (1)

Intellectual disability (1)

Intellectual Disability, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.79

M_CAP

Benign

0.0086

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

PhyloP100

2.5

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.080

REVEL

Benign

0.043

Sift

Benign

0.36

Sift4G

Benign

0.33

Polyphen

0.88

Vest4

0.37

MVP

0.13

MPC

0.081

ClinPred

0.022

GERP RS

3.4

Varity_R

0.034

gMVP

0.69

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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