Genetic Variant XM_011517326.3:c.221C>T (chr8-140458344-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The XM_011517326.3(TRAPPC9):c.221C>T(p.Ala74Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 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: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRAPPC9
XM_011517326.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.515

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04299605).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000648948.2. 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
	TRAPPC9	NM_031466.8		c.-74C>T		5_prime_UTR	Exon 1 of 23	NP_113654.5

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
TRAPPC9	ENST00000648948.2	c.-74C>T	5_prime_UTR	Exon 1 of 23	ENSP00000498020.1	Q96Q05-1
TRAPPC9	ENST00000920032.1	c.-74C>T	5_prime_UTR	Exon 1 of 21	ENSP00000590091.1
TRAPPC9	ENST00000889101.1	c.-74C>T	5_prime_UTR	Exon 1 of 21	ENSP00000559160.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1434858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711046

African (AFR)

AF:

0.00

AC:

AN:

32706

American (AMR)

AF:

0.00

AC:

AN:

39990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25412

East Asian (EAS)

AF:

0.00

AC:

AN:

38812

South Asian (SAS)

AF:

0.00

AC:

AN:

82182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099332

Other (OTH)

AF:

0.00

AC:

AN:

59366

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.7

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.42

M_CAP

Benign

0.0062

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

PhyloP100

-0.52

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.020

REVEL

Benign

0.015

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0050

Vest4

0.078

MutPred

0.21

Loss of relative solvent accessibility (P = 0.0186)

MVP

0.030

MPC

0.50

ClinPred

0.092

GERP RS

-0.54

PromoterAI

-0.0070

Neutral

(source)

gMVP

0.054

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over