rs74414386

Variant names:

• chr8-140284041-T-G
• rs74414386
• NM_001160372.4:c.1982-20A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001160372.4(TRAPPC9):​c.1982-20A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,613,698 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (38 hom.)
• Consequence: TRAPPC9 NM_001160372.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.414
• Publications: 2 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

ENSG00000308537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-140284041-T-G is Benign according to our data. Variant chr8-140284041-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2076/152228) while in subpopulation AFR AF = 0.0471 (1955/41538). AF 95% confidence interval is 0.0453. There are 50 homozygotes in GnomAd4. There are 1005 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC9	NM_001160372.4	MANE Select	c.1982-20A>C		intron	N/A	NP_001153844.1
	TRAPPC9	NM_001374682.1		c.2003-20A>C		intron	N/A	NP_001361611.1
	TRAPPC9	NM_031466.8		c.1982-20A>C		intron	N/A	NP_113654.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC9	ENST00000438773.4	TSL:1 MANE Select	c.1982-20A>C		intron	N/A	ENSP00000405060.3
	TRAPPC9	ENST00000520857.5	TSL:1	c.1511-20A>C		intron	N/A	ENSP00000430116.1
	TRAPPC9	ENST00000521667.5	TSL:1	n.387-20A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2054 AN: 152110 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0467

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00362 AC: 910 AN: 251120 AF XY: 0.00256

Gnomad AFR exome AF: 0.0478

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00155 AC: 2263 AN: 1461470 Hom.: 38 Cov.: 33 AF XY: 0.00135 AC XY: 981 AN XY: 727042

African (AFR) AF: 0.0473 AC: 1582 AN: 33462

American (AMR) AF: 0.00190 AC: 85 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86248

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53316

Middle Eastern (MID) AF: 0.00888 AC: 51 AN: 5744

European-Non Finnish (NFE) AF: 0.000238 AC: 265 AN: 1111786

Other (OTH) AF: 0.00359 AC: 217 AN: 60378

GnomAD4 genome AF: 0.0136 AC: 2076 AN: 152228 Hom.: 50 Cov.: 32 AF XY: 0.0135 AC XY: 1005 AN XY: 74420

African (AFR) AF: 0.0471 AC: 1955 AN: 41538

American (AMR) AF: 0.00491 AC: 75 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68004

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.00671 Hom.: 6

Bravo AF: 0.0156

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.28
DANN	Benign	0.35
PhyloP100		-0.41
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: rs74414386; hg19: chr8-141294140;