8-140371021-G-T

Variant names:

• chr8-140371021-G-T
• rs1554676260
• NM_001160372.4:c.1294C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001160372.4(TRAPPC9):​c.1294C>A​(p.Leu432Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L432L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRAPPC9 NM_001160372.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• intellectual disability-obesity-brain malformations-facial dysmorphism syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC9	NM_001160372.4	c.1294C>A	p.Leu432Ile	missense_variant	Exon 8 of 23	ENST00000438773.4	NP_001153844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.1294C>A	p.Leu432Ile	missense_variant	Exon 8 of 23	1	NM_001160372.4	ENSP00000405060.3
TRAPPC9	ENST00000520857.5	c.823C>A	p.Leu275Ile	missense_variant	Exon 6 of 21	1		ENSP00000430116.1
TRAPPC9	ENST00000648948.2	c.1294C>A	p.Leu432Ile	missense_variant	Exon 8 of 23			ENSP00000498020.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 14, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T;T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.6	L;L;.;L
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	.;N;N;.
REVEL	Benign	0.25
Sift	Benign	0.10	.;T;T;.
Sift4G	Uncertain	0.024	.;D;D;.
Polyphen		0.89	P;P;P;P
Vest4		0.60, 0.61
MutPred		0.37		Gain of methylation at K430 (P = 0.0688);Gain of methylation at K430 (P = 0.0688);.;Gain of methylation at K430 (P = 0.0688);
MVP		0.30
MPC		1.3
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.25
gMVP		0.51
Mutation Taster		=70/30	polymorphism

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: rs1554676260; hg19: chr8-141381120;