rs117632905

chr8-140360138-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001160372.4(TRAPPC9):c.1407C>T(p.Tyr469=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,614,206 control chromosomes in the GnomAD database, including 13 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 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (11 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.335

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 8-140360138-G-A is Benign according to our data. Variant chr8-140360138-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130614.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.335 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00148 (226/152316) while in subpopulation EAS AF= 0.00231 (12/5194). AF 95% confidence interval is 0.00133. There are 2 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.1407C>T	p.Tyr469=	synonymous_variant	9/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.1407C>T	p.Tyr469=	synonymous_variant	9/23	1	NM_001160372.4	P1
TRAPPC9	ENST00000520857.5	c.939C>T	p.Tyr313=	synonymous_variant	7/21	1
TRAPPC9	ENST00000648948.2	c.1407C>T	p.Tyr469=	synonymous_variant	9/23			P1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00210 AC: 528 AN: 251480 Hom.: 5 AF XY: 0.00207 AC XY: 281 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.000949

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000910 AC: 1330 AN: 1461890 Hom.: 11 Cov.: 31 AF XY: 0.000908 AC XY: 660 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000691 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TRAPPC9: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

Intellectual Disability, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 23, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	9.7
Dann	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs117632905; hg19: chr8-141370237;