chr8-140252770-C-T

Variant names:

• chr8-140252770-C-T
• rs11166964
• NM_001160372.4:c.2431+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374682.1(TRAPPC9):​c.2452+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,612,806 control chromosomes in the GnomAD database, including 13,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1083 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12511 hom.)
• Consequence: TRAPPC9 NM_001374682.1 splice_region, intron
• Scores: Splicing: ADA: 0.00002083
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.21
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-140252770-C-T is Benign according to our data. Variant chr8-140252770-C-T is described in ClinVar as Benign. ClinVar VariationId is 130626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

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.2431+7G>A		splice_region intron	N/A	NP_001153844.1
	TRAPPC9	NM_001374682.1		c.2452+7G>A		splice_region intron	N/A	NP_001361611.1
	TRAPPC9	NM_031466.8		c.2431+7G>A		splice_region intron	N/A	NP_113654.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC9	ENST00000438773.4	TSL:1 MANE Select	c.2431+7G>A		splice_region intron	N/A	ENSP00000405060.3
	TRAPPC9	ENST00000520857.5	TSL:1	c.1960+7G>A		splice_region intron	N/A	ENSP00000430116.1
	TRAPPC9	ENST00000521667.5	TSL:1	n.836+7G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16023 AN: 151904 Hom.: 1077 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.0701

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.127 AC: 31828 AN: 249920 AF XY: 0.123

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.00218

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.124 AC: 181300 AN: 1460784 Hom.: 12511 Cov.: 32 AF XY: 0.123 AC XY: 89080 AN XY: 726758

African (AFR) AF: 0.0282 AC: 945 AN: 33476

American (AMR) AF: 0.235 AC: 10513 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2854 AN: 26132

East Asian (EAS) AF: 0.00164 AC: 65 AN: 39698

South Asian (SAS) AF: 0.0775 AC: 6688 AN: 86248

European-Finnish (FIN) AF: 0.169 AC: 8915 AN: 52764

Middle Eastern (MID) AF: 0.0832 AC: 480 AN: 5768

European-Non Finnish (NFE) AF: 0.130 AC: 144168 AN: 1111622

Other (OTH) AF: 0.111 AC: 6672 AN: 60368

GnomAD4 genome AF: 0.106 AC: 16040 AN: 152022 Hom.: 1083 Cov.: 32 AF XY: 0.107 AC XY: 7979 AN XY: 74308

African (AFR) AF: 0.0352 AC: 1459 AN: 41480

American (AMR) AF: 0.172 AC: 2624 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3472

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5166

South Asian (SAS) AF: 0.0699 AC: 336 AN: 4806

European-Finnish (FIN) AF: 0.178 AC: 1881 AN: 10540

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9024 AN: 67958

Other (OTH) AF: 0.0985 AC: 208 AN: 2112

Alfa AF: 0.121 Hom.: 2729

Bravo AF: 0.102

Asia WGS AF: 0.0590 AC: 208 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.120

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Intellectual disability, autosomal recessive 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.25
DANN	Benign	0.70
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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: rs11166964; hg19: chr8-141262869;