19-45165188-T-C

Variant names:

• chr19-45165188-T-C
• rs145458791
• NM_001270891.2:c.91A>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001270891.2(TRAPPC6A):​c.91A>G​(p.Lys31Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,602,732 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TRAPPC6A NM_001270891.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.913

Genes affected

TRAPPC6A (HGNC:23069): (trafficking protein particle complex subunit 6A) This gene encodes a component of the trafficking protein particle complex, which tethers transport vesicles to the cis-Golgi membrane. Loss of expression of the related gene in mouse affects coat and eye pigmentation, suggesting that the encoded protein may be involved in melanosome biogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

MARK4 (HGNC:13538): (microtubule affinity regulating kinase 4) This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer's disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039969683).
• BP6: Variant 19-45165188-T-C is Benign according to our data. Variant chr19-45165188-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3056542.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC6A	NM_001270891.2	c.91A>G	p.Lys31Glu	missense_variant	Exon 2 of 6	ENST00000585934.1	NP_001257820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC6A	ENST00000585934.1	c.91A>G	p.Lys31Glu	missense_variant	Exon 2 of 6	1	NM_001270891.2	ENSP00000468612.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152164 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000225 AC: 51 AN: 226936 Hom.: 0 AF XY: 0.000203 AC XY: 25 AN XY: 123234

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.0000912

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000101 AC: 146 AN: 1450450 Hom.: 0 Cov.: 32 AF XY: 0.0000860 AC XY: 62 AN XY: 720906

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.000390

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000300

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152282 Hom.: 3 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74480

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000239 Hom.: 1

Bravo AF: 0.00153

ESP6500AA AF: 0.00455 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TRAPPC6A-related disorder Benign:1

Jul 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.60
DEOGEN2	Benign	0.10	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.78	.;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.22	N;.
REVEL	Benign	0.057
Sift	Benign	1.0	T;.
Sift4G	Benign	0.97	T;T
Polyphen		0.0090	B;B
Vest4		0.33
MVP		0.21
MPC		0.11
ClinPred		0.0033	T
GERP RS		3.4
Varity_R		0.21
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs145458791; hg19: chr19-45668446;