19-45165188-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 15/22 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

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.913

Publications

2 publications found

Variant links:

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]

TRAPPC6A links:

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]

MARK4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

MARK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 link	c.91A>G	p.Lys31Glu	missense_variant	Exon 2 of 6	ENST00000585934.1	NP_001257820.1	O75865-1B7TZ90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC6A	ENST00000585934.1 link	c.91A>G	p.Lys31Glu	missense_variant	Exon 2 of 6	1	NM_001270891.2	ENSP00000468612.1		O75865-1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152164

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000225

AC:

AN:

226936

AF XY:

0.000203

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000860

AC XY:

AN XY:

720906

show subpopulations

African (AFR)

AF:

0.00338

AC:

111

AN:

32840

American (AMR)

AF:

0.000390

AC:

AN:

43622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25930

East Asian (EAS)

AF:

0.00

AC:

AN:

38414

South Asian (SAS)

AF:

0.00

AC:

AN:

84424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107048

Other (OTH)

AF:

0.000300

AC:

AN:

59934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00118

AC:

179

AN:

152282

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00358

AC:

149

AN:

41566

American (AMR)

AF:

0.00176

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000522

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.00455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

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

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.10

.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.58

T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.78

.;N

PhyloP100

0.91

PrimateAI

Uncertain

0.55

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

GERP RS

3.4

Varity_R

0.21

gMVP

0.22

Mutation Taster

=85/15

polymorphism

(source)

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

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19-45165188-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over