NM_001160372.4:c.2796C>T

Variant names:

• chr8-139988740-G-A
• rs145607512
• NM_001160372.4:c.2796C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001160372.4(TRAPPC9):​c.2796C>T​(p.Ala932Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,549,832 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.728
• Publications: 0 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.014).
• BP6: Variant 8-139988740-G-A is Benign according to our data. Variant chr8-139988740-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 362069.
• BP7: Synonymous conserved (PhyloP=-0.728 with no splicing effect.

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.2796C>T	p.Ala932Ala	synonymous	Exon 19 of 23	NP_001153844.1	Q96Q05-1
	TRAPPC9	NM_001374682.1		c.2817C>T	p.Ala939Ala	synonymous	Exon 20 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.2796C>T	p.Ala932Ala	synonymous	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.2796C>T	p.Ala932Ala	synonymous	Exon 19 of 23	ENSP00000405060.3	Q96Q05-1
	TRAPPC9	ENST00000520857.5	TSL:1	c.2325C>T	p.Ala775Ala	synonymous	Exon 17 of 21	ENSP00000430116.1	H0YBR0
	TRAPPC9	ENST00000521667.5	TSL:1	n.1201C>T		non_coding_transcript_exon	Exon 8 of 12

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000552 AC: 86 AN: 155890 AF XY: 0.000426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00622

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000363 AC: 508 AN: 1397538 Hom.: 1 Cov.: 34 AF XY: 0.000386 AC XY: 266 AN XY: 689432

African (AFR) AF: 0.0000317 AC: 1 AN: 31554

American (AMR) AF: 0.000168 AC: 6 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00703 AC: 177 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48824

Middle Eastern (MID) AF: 0.000565 AC: 3 AN: 5310

European-Non Finnish (NFE) AF: 0.000262 AC: 282 AN: 1078126

Other (OTH) AF: 0.000622 AC: 36 AN: 57920

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74464

African (AFR) AF: 0.0000481 AC: 2 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000656 Hom.: 0

Bravo AF: 0.000382

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	-0.37
CADD	Benign	5.2
DANN	Benign	0.78
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs145607512; hg19: chr8-140998948;