8-139988739-C-T

Variant names:

• chr8-139988739-C-T
• rs114949291
• NM_001160372.4:c.2797G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001160372.4(TRAPPC9):​c.2797G>A​(p.Gly933Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,550,178 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G933G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (61 hom.)
• Consequence: TRAPPC9 NM_001160372.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.77
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004834801).
• BP6: Variant 8-139988739-C-T is Benign according to our data. Variant chr8-139988739-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130629.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00675 (1028/152226) while in subpopulation SAS AF = 0.0245 (118/4814). AF 95% confidence interval is 0.0209. There are 5 homozygotes in GnomAd4. There are 509 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.2797G>A	p.Gly933Ser	missense	Exon 19 of 23	NP_001153844.1
	TRAPPC9	NM_001374682.1		c.2818G>A	p.Gly940Ser	missense	Exon 20 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.2797G>A	p.Gly933Ser	missense	Exon 19 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.2797G>A	p.Gly933Ser	missense	Exon 19 of 23	ENSP00000405060.3
	TRAPPC9	ENST00000520857.5	TSL:1	c.2326G>A	p.Gly776Ser	missense	Exon 17 of 21	ENSP00000430116.1
	TRAPPC9	ENST00000521667.5	TSL:1	n.1202G>A		non_coding_transcript_exon	Exon 8 of 12

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1025 AN: 152108 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00574 AC: 895 AN: 155810 AF XY: 0.00689

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0000886

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000796

Gnomad OTH exome AF: 0.00386

GnomAD4 exome AF: 0.00274 AC: 3825 AN: 1397952 Hom.: 61 Cov.: 34 AF XY: 0.00346 AC XY: 2386 AN XY: 689596

African (AFR) AF: 0.0237 AC: 748 AN: 31568

American (AMR) AF: 0.00174 AC: 62 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 88 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35734

South Asian (SAS) AF: 0.0256 AC: 2028 AN: 79194

European-Finnish (FIN) AF: 0.0000410 AC: 2 AN: 48770

Middle Eastern (MID) AF: 0.0128 AC: 68 AN: 5298

European-Non Finnish (NFE) AF: 0.000541 AC: 584 AN: 1078576

Other (OTH) AF: 0.00421 AC: 244 AN: 57928

GnomAD4 genome AF: 0.00675 AC: 1028 AN: 152226 Hom.: 5 Cov.: 33 AF XY: 0.00684 AC XY: 509 AN XY: 74422

African (AFR) AF: 0.0185 AC: 769 AN: 41528

American (AMR) AF: 0.00399 AC: 61 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68024

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00311 Hom.: 9

Bravo AF: 0.00663

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0139 AC: 54

ESP6500EA AF: 0.000685 AC: 5

ExAC AF: 0.00690 AC: 305

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	0.090
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.042
Sift	Benign	0.21	T
Sift4G	Benign	0.60	T
Polyphen		0.0050	B
Vest4		0.29
MVP		0.36
MPC		0.085
ClinPred		0.015	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.12
Mutation Taster		=95/5	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: rs114949291; hg19: chr8-140998947; COSMIC: COSV66905768; COSMIC: COSV66905768;