rs10865541

Variant names:

• chr2-3388304-T-A
• rs10865541
• NM_016030.6:c.681T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-3388304-T-A
• chr2-3388304-T-C
• chr2-3388304-T-G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_016030.6(TRAPPC12):​c.681T>A​(p.Phe227Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000934 in 1,606,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F227S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: TRAPPC12 NM_016030.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.72
• Publications: 26 publications found

Genes affected

TRAPPC12 (HGNC:24284): (trafficking protein particle complex subunit 12) Involved in several processes, including endoplasmic reticulum to Golgi vesicle-mediated transport; positive regulation of protein localization to kinetochore; and regulation of kinetochore assembly. Located in Golgi apparatus; kinetochore; and nucleoplasm. Part of TRAPP complex. Colocalizes with endoplasmic reticulum-Golgi intermediate compartment and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC12 Gene-Disease associations (from GenCC):

• early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2925405).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016030.6. 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
	TRAPPC12	NM_016030.6	MANE Select	c.681T>A	p.Phe227Leu	missense	Exon 2 of 12	NP_057114.5
	TRAPPC12	NM_001321102.2		c.681T>A	p.Phe227Leu	missense	Exon 2 of 12	NP_001308031.1	Q8WVT3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC12	ENST00000324266.10	TSL:1 MANE Select	c.681T>A	p.Phe227Leu	missense	Exon 2 of 12	ENSP00000324318.5	Q8WVT3
	TRAPPC12	ENST00000858088.1		c.681T>A	p.Phe227Leu	missense	Exon 2 of 13	ENSP00000528147.1
	TRAPPC12	ENST00000964175.1		c.681T>A	p.Phe227Leu	missense	Exon 2 of 13	ENSP00000634234.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000297 AC: 7 AN: 235766 AF XY: 0.0000312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1454836 Hom.: 0 Cov.: 62 AF XY: 0.00000829 AC XY: 6 AN XY: 723756

African (AFR) AF: 0.00 AC: 0 AN: 32246

American (AMR) AF: 0.00 AC: 0 AN: 44276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39002

South Asian (SAS) AF: 0.000129 AC: 11 AN: 85512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109256

Other (OTH) AF: 0.00 AC: 0 AN: 60110

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151960 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41484

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67900

Other (OTH) AF: 0.00 AC: 0 AN: 2108

ExAC AF: 0.0000415 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Uncertain	0.013	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.11		Gain of glycosylation at T229 (P = 0.1087)
MVP		0.62
MPC		0.96
ClinPred		0.44	T
GERP RS		3.3
Varity_R		0.21
gMVP		0.43
Mutation Taster		=63/37	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: rs10865541; hg19: chr2-3392075;