8-140300545-G-T

Variant names:

• chr8-140300545-G-T
• rs12549048
• NM_001160372.4:c.1692C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001160372.4(TRAPPC9):​c.1692C>A​(p.Asn564Lys) 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. 14/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N564N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRAPPC9 NM_001160372.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.239
• Publications: 20 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: 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

ACMG classification

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=0.048566073).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC9	NM_001160372.4	MANE Select	c.1692C>A	p.Asn564Lys	missense	Exon 11 of 23	NP_001153844.1	Q96Q05-1
	TRAPPC9	NM_001374682.1		c.1713C>A	p.Asn571Lys	missense	Exon 12 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.1692C>A	p.Asn564Lys	missense	Exon 11 of 23	NP_113654.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC9	ENST00000438773.4	TSL:1 MANE Select	c.1692C>A	p.Asn564Lys	missense	Exon 11 of 23	ENSP00000405060.3	Q96Q05-1
	TRAPPC9	ENST00000520857.5	TSL:1	c.1221C>A	p.Asn407Lys	missense	Exon 9 of 21	ENSP00000430116.1	H0YBR0
	TRAPPC9	ENST00000889106.1		c.1713C>A	p.Asn571Lys	missense	Exon 12 of 24	ENSP00000559165.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		0.24
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.051
Sift	Benign	0.19	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.34		Gain of methylation at N564 (P = 0.0173)
MVP		0.23
MPC		0.65
ClinPred		0.43	T
GERP RS		3.9
Varity_R		0.038
gMVP		0.24
Mutation Taster		=79/21	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: rs12549048; hg19: chr8-141310644;