chr8-140451167-A-G

Variant names:

• chr8-140451167-A-G
• rs3735801
• NM_001160372.4:c.207T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001160372.4(TRAPPC9):​c.207T>C​(p.Gly69Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,613,186 control chromosomes in the GnomAD database, including 254,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (23735 hom., cov: 29)
  • Exomes 𝑓: 0.56 (230517 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.97
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-140451167-A-G is Benign according to our data. Variant chr8-140451167-A-G is described in ClinVar as Benign. ClinVar VariationId is 130634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC9	NM_001160372.4	MANE Select	c.207T>C	p.Gly69Gly	synonymous	Exon 2 of 23	NP_001153844.1
	TRAPPC9	NM_001374682.1		c.207T>C	p.Gly69Gly	synonymous	Exon 2 of 24	NP_001361611.1
	TRAPPC9	NM_031466.8		c.207T>C	p.Gly69Gly	synonymous	Exon 2 of 23	NP_113654.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC9	ENST00000438773.4	TSL:1 MANE Select	c.207T>C	p.Gly69Gly	synonymous	Exon 2 of 23	ENSP00000405060.3
	TRAPPC9	ENST00000648948.2		c.207T>C	p.Gly69Gly	synonymous	Exon 2 of 23	ENSP00000498020.1
	TRAPPC9	ENST00000520857.5	TSL:1	c.-238T>C		upstream_gene	N/A	ENSP00000430116.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84470 AN: 151236 Hom.: 23713 Cov.: 29

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.539 AC: 135478 AN: 251340 AF XY: 0.544

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.542

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.566

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.560 AC: 818668 AN: 1461832 Hom.: 230517 Cov.: 75 AF XY: 0.560 AC XY: 407521 AN XY: 727224

African (AFR) AF: 0.540 AC: 18067 AN: 33480

American (AMR) AF: 0.389 AC: 17397 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 15942 AN: 26136

East Asian (EAS) AF: 0.532 AC: 21109 AN: 39700

South Asian (SAS) AF: 0.550 AC: 47455 AN: 86256

European-Finnish (FIN) AF: 0.598 AC: 31942 AN: 53394

Middle Eastern (MID) AF: 0.542 AC: 3126 AN: 5768

European-Non Finnish (NFE) AF: 0.567 AC: 629974 AN: 1111984

Other (OTH) AF: 0.557 AC: 33656 AN: 60394

GnomAD4 genome AF: 0.558 AC: 84530 AN: 151354 Hom.: 23735 Cov.: 29 AF XY: 0.557 AC XY: 41157 AN XY: 73908

African (AFR) AF: 0.551 AC: 22709 AN: 41236

American (AMR) AF: 0.491 AC: 7458 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2097 AN: 3464

East Asian (EAS) AF: 0.531 AC: 2723 AN: 5126

South Asian (SAS) AF: 0.558 AC: 2650 AN: 4746

European-Finnish (FIN) AF: 0.597 AC: 6263 AN: 10498

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38845 AN: 67778

Other (OTH) AF: 0.559 AC: 1176 AN: 2102

Alfa AF: 0.562 Hom.: 84247

Bravo AF: 0.545

Asia WGS AF: 0.537 AC: 1863 AN: 3478

EpiCase AF: 0.566

EpiControl AF: 0.566

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal recessive 13 (1)
-	-	1	Intellectual Disability, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.35
DANN	Benign	0.60
PhyloP100		-2.0
PromoterAI		-0.0078	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs3735801; hg19: chr8-141461266; COSMIC: COSV66911941; COSMIC: COSV66911941;