6-116540445-G-T

Variant names:

• chr6-116540445-G-T
• rs1416406707
• NM_001139444.3:c.158C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001139444.3(TRAPPC3L):​c.158C>A​(p.Thr53Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000357 in 1,399,030 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T53M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (1 hom.)
• Consequence: TRAPPC3L NM_001139444.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.59
• Publications: 1 publications found

Genes affected

TRAPPC3L (HGNC:21090): (trafficking protein particle complex subunit 3L) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport and intra-Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

CALHM4 (HGNC:21094): (calcium homeostasis modulator family member 4) Predicted to enable cation channel activity. Predicted to be involved in cation transmembrane transport. Predicted to be integral component of membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001139444.3. 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
	TRAPPC3L	NM_001139444.3	MANE Select	c.158C>A	p.Thr53Lys	missense	Exon 3 of 5	NP_001132916.1	Q5T215-1
	CALHM4	NM_001256887.3		c.-140-3320G>T		intron	N/A	NP_001243816.1	Q5JW98-3
	CALHM4	NM_001256888.3		c.-49-3320G>T		intron	N/A	NP_001243817.1	Q5JW98-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC3L	ENST00000368602.4	TSL:5 MANE Select	c.158C>A	p.Thr53Lys	missense	Exon 3 of 5	ENSP00000357591.3	Q5T215-1
	CALHM4	ENST00000405399.5	TSL:1	c.-140-3320G>T		intron	N/A	ENSP00000385836.1	Q5JW98-3
	CALHM4	ENST00000368597.6	TSL:1	c.-108-3320G>T		intron	N/A	ENSP00000357586.2	Q5JW98-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399030 Hom.: 1 Cov.: 30 AF XY: 0.00000580 AC XY: 4 AN XY: 690034

African (AFR) AF: 0.0000634 AC: 2 AN: 31556

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49272

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078712

Other (OTH) AF: 0.0000172 AC: 1 AN: 57980

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0077	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.52	P
Vest4		0.56
MutPred		0.45		Gain of ubiquitination at T53 (P = 0.03)
MVP		0.20
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.44
gMVP		0.85
Mutation Taster		=80/20	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: rs1416406707; hg19: chr6-116861608;