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. 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: 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: 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

Selected	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
	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

Selected	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
	TRAPPC9	ENST00000520857.5	TSL:1	c.1221C>A	p.Asn407Lys	missense	Exon 9 of 21	ENSP00000430116.1
	TRAPPC9	ENST00000648948.2		c.1692C>A	p.Asn564Lys	missense	Exon 11 of 23	ENSP00000498020.1

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;