rs147182402

Variant names:

• chr8-140451234-C-T
• rs147182402
• NM_001160372.4:c.140G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001160372.4(TRAPPC9):​c.140G>A​(p.Arg47Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000371 in 1,613,914 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: TRAPPC9 NM_001160372.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.81
• Publications: 12 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10150102).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00038 (556/1461636) while in subpopulation MID AF = 0.0104 (60/5768). AF 95% confidence interval is 0.0083. There are 1 homozygotes in GnomAdExome4. There are 289 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.140G>A	p.Arg47Gln	missense	Exon 2 of 23	NP_001153844.1	Q96Q05-1
	TRAPPC9	NM_001374682.1		c.140G>A	p.Arg47Gln	missense	Exon 2 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.140G>A	p.Arg47Gln	missense	Exon 2 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.140G>A	p.Arg47Gln	missense	Exon 2 of 23	ENSP00000405060.3	Q96Q05-1
	TRAPPC9	ENST00000889106.1		c.140G>A	p.Arg47Gln	missense	Exon 2 of 24	ENSP00000559165.1
	TRAPPC9	ENST00000648948.2		c.140G>A	p.Arg47Gln	missense	Exon 2 of 23	ENSP00000498020.1	Q96Q05-1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000331 AC: 83 AN: 251040 AF XY: 0.000398

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000380 AC: 556 AN: 1461636 Hom.: 1 Cov.: 35 AF XY: 0.000397 AC XY: 289 AN XY: 727116

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.0000940 AC: 5 AN: 53176

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.000355 AC: 395 AN: 1112002

Other (OTH) AF: 0.000679 AC: 41 AN: 60394

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74450

African (AFR) AF: 0.0000962 AC: 4 AN: 41562

American (AMR) AF: 0.000392 AC: 6 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Intellectual disability, autosomal recessive 13 (4)
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual Disability, Recessive (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.098
Sift	Benign	0.20	T
Sift4G	Benign	0.25	T
Polyphen		0.98	D
Vest4		0.61
MVP		0.34
MPC		1.5
ClinPred		0.072	T
GERP RS		4.4
PromoterAI		0.0045	Neutral
Varity_R		0.062
gMVP		0.47
Mutation Taster		=90/10	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: rs147182402; hg19: chr8-141461333; COSMIC: COSV101227611; COSMIC: COSV101227611;