8-139732009-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BS1 BS2

The NM_001374682.1(TRAPPC9):​c.3270C>T​(p.Phe1090Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,596,098 control chromosomes in the GnomAD database, including 64 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (61 hom.)
• Consequence: TRAPPC9 NM_001374682.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 8-139732009-G-A is Benign according to our data. Variant chr8-139732009-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130632.
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.005 (762/152352) while in subpopulation NFE AF = 0.00747 (508/68032). AF 95% confidence interval is 0.00693. There are 3 homozygotes in GnomAd4. There are 343 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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>T	p.Phe1083Phe	synonymous	Exon 22 of 23	NP_001153844.1
	TRAPPC9	NM_001374682.1		c.3270C>T	p.Phe1090Phe	synonymous	Exon 23 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.3249C>T	p.Phe1083Phe	synonymous	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>T	p.Phe1083Phe	synonymous	Exon 22 of 23	ENSP00000405060.3
	TRAPPC9	ENST00000520857.5	TSL:1	c.2778C>T	p.Phe926Phe	synonymous	Exon 20 of 21	ENSP00000430116.1
	TRAPPC9	ENST00000521667.5	TSL:1	n.1654C>T		non_coding_transcript_exon	Exon 11 of 12

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 762 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00747

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00617 AC: 1351 AN: 218814 AF XY: 0.00642

Gnomad AFR exome AF: 0.00159

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.00480

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.00814

Gnomad OTH exome AF: 0.00691

GnomAD4 exome AF: 0.00810 AC: 11701 AN: 1443746 Hom.: 61 Cov.: 32 AF XY: 0.00801 AC XY: 5738 AN XY: 716254

African (AFR) AF: 0.00115 AC: 38 AN: 33158

American (AMR) AF: 0.00481 AC: 204 AN: 42392

Ashkenazi Jewish (ASJ) AF: 0.00471 AC: 121 AN: 25714

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

South Asian (SAS) AF: 0.00610 AC: 508 AN: 83238

European-Finnish (FIN) AF: 0.00899 AC: 467 AN: 51920

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5744

European-Non Finnish (NFE) AF: 0.00895 AC: 9874 AN: 1103066

Other (OTH) AF: 0.00794 AC: 474 AN: 59662

GnomAD4 genome AF: 0.00500 AC: 762 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.00460 AC XY: 343 AN XY: 74496

African (AFR) AF: 0.00176 AC: 73 AN: 41590

American (AMR) AF: 0.00327 AC: 50 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4826

European-Finnish (FIN) AF: 0.00697 AC: 74 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00747 AC: 508 AN: 68032

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00586 Hom.: 1

Bravo AF: 0.00492

Asia WGS AF: 0.00260 AC: 9 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)
-	-	1	TRAPPC9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.60
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112551069; hg19: chr8-140744252;