8-140371151-G-A

Variant names:

• chr8-140371151-G-A
• rs148976893
• NM_001160372.4:c.1164C>T

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.1164C>T​(p.Tyr388Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.000821 in 1,613,538 control chromosomes in the GnomAD database, including 4 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 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (3 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.94
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 8-140371151-G-A is Benign according to our data. Variant chr8-140371151-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212414.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00126 (192/152280) while in subpopulation NFE AF = 0.0016 (109/68046). AF 95% confidence interval is 0.00136. There are 1 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1164C>T	p.Tyr388Tyr	synonymous	Exon 8 of 23	NP_001153844.1	Q96Q05-1
	TRAPPC9	NM_001374682.1		c.1185C>T	p.Tyr395Tyr	synonymous	Exon 9 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.1164C>T	p.Tyr388Tyr	synonymous	Exon 8 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.1164C>T	p.Tyr388Tyr	synonymous	Exon 8 of 23	ENSP00000405060.3	Q96Q05-1
	TRAPPC9	ENST00000520857.5	TSL:1	c.693C>T	p.Tyr231Tyr	synonymous	Exon 6 of 21	ENSP00000430116.1	H0YBR0
	TRAPPC9	ENST00000889106.1		c.1185C>T	p.Tyr395Tyr	synonymous	Exon 9 of 24	ENSP00000559165.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152280 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00113 AC: 281 AN: 248294 AF XY: 0.00109

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00618

Gnomad NFE exome AF: 0.000987

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000775 AC: 1133 AN: 1461258 Hom.: 3 Cov.: 32 AF XY: 0.000813 AC XY: 591 AN XY: 726914

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000896 AC: 4 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86200

European-Finnish (FIN) AF: 0.00539 AC: 287 AN: 53246

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

European-Non Finnish (NFE) AF: 0.000674 AC: 749 AN: 1111760

Other (OTH) AF: 0.000663 AC: 40 AN: 60368

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152280 Hom.: 1 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74404

African (AFR) AF: 0.0000241 AC: 1 AN: 41482

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68046

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.000646

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.6
DANN	Benign	0.55
PhyloP100		3.9
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)		0.0		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: rs148976893; hg19: chr8-141381250;