8-139732009-G-C

Variant names:

• chr8-139732009-G-C
• rs112551069
• NM_001160372.4:c.3249C>G

Variant summary

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

The NM_001374682.1(TRAPPC9):​c.3270C>G​(p.Phe1090Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000097 in 1,443,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. F1090F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: TRAPPC9 NM_001374682.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.51
• Publications: 1 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374682.1. 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.3249C>G	p.Phe1083Leu	missense	Exon 22 of 23	NP_001153844.1
	TRAPPC9	NM_001374682.1		c.3270C>G	p.Phe1090Leu	missense	Exon 23 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.3249C>G	p.Phe1083Leu	missense	Exon 22 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.3249C>G	p.Phe1083Leu	missense	Exon 22 of 23	ENSP00000405060.3
	TRAPPC9	ENST00000520857.5	TSL:1	c.2778C>G	p.Phe926Leu	missense	Exon 20 of 21	ENSP00000430116.1
	TRAPPC9	ENST00000521667.5	TSL:1	n.1654C>G		non_coding_transcript_exon	Exon 11 of 12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000274 AC: 6 AN: 218814 AF XY: 0.0000339

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000970 AC: 14 AN: 1443764 Hom.: 0 Cov.: 32 AF XY: 0.0000126 AC XY: 9 AN XY: 716260

African (AFR) AF: 0.00 AC: 0 AN: 33158

American (AMR) AF: 0.000118 AC: 5 AN: 42396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.00 AC: 0 AN: 38852

South Asian (SAS) AF: 0.00 AC: 0 AN: 83238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51922

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103076

Other (OTH) AF: 0.0000503 AC: 3 AN: 59664

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.21
Sift	Benign	0.22	T
Sift4G	Benign	0.72	T
Polyphen		0.68	P
Vest4		0.95
MutPred		0.72		Gain of sheet (P = 0.0827)
MVP		0.18
MPC		0.41
ClinPred		0.10	T
GERP RS		0.40
Varity_R		0.12
gMVP		0.74
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112551069; hg19: chr8-140744252;