6-116545474-A-T

Variant names:

• chr6-116545474-A-T
• rs1355419594
• NM_001139444.3:c.41T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001139444.3(TRAPPC3L):​c.41T>A​(p.Ile14Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000717 in 1,393,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. I14T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TRAPPC3L NM_001139444.3 missense, splice_region
• Scores: Splicing: ADA: 0.8280
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

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.41T>A	p.Ile14Lys	missense splice_region	Exon 1 of 5	NP_001132916.1	Q5T215-1
	CALHM4	NM_001256887.3		c.-33+1602A>T		intron	N/A	NP_001243816.1	Q5JW98-3
	CALHM4	NM_001256888.3		c.59+1602A>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.41T>A	p.Ile14Lys	missense splice_region	Exon 1 of 5	ENSP00000357591.3	Q5T215-1
	CALHM4	ENST00000405399.5	TSL:1	c.-33+1602A>T		intron	N/A	ENSP00000385836.1	Q5JW98-3
	CALHM4	ENST00000368597.6	TSL:1	c.-1+1602A>T		intron	N/A	ENSP00000357586.2	Q5JW98-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000653 AC: 1 AN: 153106 AF XY: 0.00

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: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393770 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 687394

African (AFR) AF: 0.00 AC: 0 AN: 31400

American (AMR) AF: 0.00 AC: 0 AN: 35152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25072

East Asian (EAS) AF: 0.00 AC: 0 AN: 35558

South Asian (SAS) AF: 0.00 AC: 0 AN: 78326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075674

Other (OTH) AF: 0.00 AC: 0 AN: 57776

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.93	P
Vest4		0.79
MutPred		0.56		Gain of disorder (P = 0.0031)
MVP		0.16
ClinPred		0.96	D
GERP RS		5.8
PromoterAI		0.20	Neutral
Varity_R		0.63
gMVP		0.96
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Pathogenic	0.76
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: rs1355419594; hg19: chr6-116866637;