rs117685875

Variant names:

• chr8-140287720-G-A
• rs117685875
• NM_001160372.4:c.1869C>T

Variant summary

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

The NM_001160372.4(TRAPPC9):​c.1869C>T​(p.Ser623Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,128 control chromosomes in the GnomAD database, including 190 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0096 (11 hom., cov: 32)
  • Exomes 𝑓: 0.014 (179 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.873
• 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: 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 8-140287720-G-A is Benign according to our data. Variant chr8-140287720-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130624.
• BP7: Synonymous conserved (PhyloP=-0.873 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0096 (1461/152266) while in subpopulation NFE AF = 0.0159 (1082/68016). AF 95% confidence interval is 0.0151. There are 11 homozygotes in GnomAd4. There are 674 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1869C>T	p.Ser623Ser	synonymous	Exon 13 of 23	NP_001153844.1	Q96Q05-1
	TRAPPC9	NM_001374682.1		c.1890C>T	p.Ser630Ser	synonymous	Exon 14 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.1869C>T	p.Ser623Ser	synonymous	Exon 13 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.1869C>T	p.Ser623Ser	synonymous	Exon 13 of 23	ENSP00000405060.3	Q96Q05-1
	TRAPPC9	ENST00000520857.5	TSL:1	c.1398C>T	p.Ser466Ser	synonymous	Exon 11 of 21	ENSP00000430116.1	H0YBR0
	TRAPPC9	ENST00000521667.5	TSL:1	n.274C>T		non_coding_transcript_exon	Exon 2 of 12

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1462 AN: 152148 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00989

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00818

GnomAD2 exomes AF: 0.00841 AC: 2114 AN: 251304 AF XY: 0.00797

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00602

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.0138 AC: 20214 AN: 1461862 Hom.: 179 Cov.: 32 AF XY: 0.0133 AC XY: 9669 AN XY: 727230

African (AFR) AF: 0.00305 AC: 102 AN: 33480

American (AMR) AF: 0.00438 AC: 196 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86258

European-Finnish (FIN) AF: 0.00669 AC: 357 AN: 53396

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0169 AC: 18771 AN: 1112004

Other (OTH) AF: 0.0120 AC: 722 AN: 60396

GnomAD4 genome AF: 0.00960 AC: 1461 AN: 152266 Hom.: 11 Cov.: 32 AF XY: 0.00905 AC XY: 674 AN XY: 74452

African (AFR) AF: 0.00308 AC: 128 AN: 41576

American (AMR) AF: 0.00987 AC: 151 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0159 AC: 1082 AN: 68016

Other (OTH) AF: 0.00810 AC: 17 AN: 2100

Alfa AF: 0.0133 Hom.: 35

Bravo AF: 0.0100

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.46
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs117685875; hg19: chr8-141297819;