2-3388304-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016030.6(TRAPPC12):​c.681T>G​(p.Phe227Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRAPPC12 NM_016030.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC12	NM_016030.6	c.681T>G	p.Phe227Leu	missense_variant	Exon 2 of 12	ENST00000324266.10	NP_057114.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC12	ENST00000324266.10	c.681T>G	p.Phe227Leu	missense_variant	Exon 2 of 12	1	NM_016030.6	ENSP00000324318.5
TRAPPC12	ENST00000382110.6	c.681T>G	p.Phe227Leu	missense_variant	Exon 2 of 12	2		ENSP00000371544.2
TRAPPC12	ENST00000411973.3	n.177T>G		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000405626.1
TRAPPC12	ENST00000482645.1	n.842T>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000424 AC: 1 AN: 235766 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128406

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 SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454836 Hom.: 0 Cov.: 62 AF XY: 0.00 AC XY: 0 AN XY: 723756

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.085	T;T
Polyphen		1.0	D;D
Vest4		0.60
MutPred		0.11		Gain of glycosylation at T229 (P = 0.1087);Gain of glycosylation at T229 (P = 0.1087);
MVP		0.62
MPC		0.96
ClinPred		0.76	D
GERP RS		3.3
Varity_R		0.21
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs10865541; hg19: chr2-3392075;