chr19-45164241-A-T

Position:

• chr19-45164241-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000585934.1(TRAPPC6A):​c.277T>A​(p.Tyr93Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,603,892 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (13 hom.)
• Consequence: TRAPPC6A ENST00000585934.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 1.60

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010287464).
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAPPC6A	NM_001270891.2	c.277T>A	p.Tyr93Asn	missense_variant	4/6	ENST00000585934.1	NP_001257820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAPPC6A	ENST00000585934.1	c.277T>A	p.Tyr93Asn	missense_variant	4/6	1	NM_001270891.2	ENSP00000468612.1

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 151960 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00224 AC: 533 AN: 238252 Hom.: 1 AF XY: 0.00209 AC XY: 269 AN XY: 128668

Gnomad AFR exome AF: 0.000509

Gnomad AMR exome AF: 0.000719

Gnomad ASJ exome AF: 0.000665

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000141

Gnomad FIN exome AF: 0.00825

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00287 AC: 4170 AN: 1451814 Hom.: 13 Cov.: 32 AF XY: 0.00275 AC XY: 1980 AN XY: 721262

Gnomad4 AFR exome AF: 0.000571

Gnomad4 AMR exome AF: 0.000776

Gnomad4 ASJ exome AF: 0.000631

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000829

Gnomad4 FIN exome AF: 0.00740

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152078 Hom.: 1 Cov.: 33 AF XY: 0.00241 AC XY: 179 AN XY: 74360

Gnomad4 AFR AF: 0.000507

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00829

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00235 Hom.: 0

Bravo AF: 0.00194

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 17, 2020	- -

TRAPPC6A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 10, 2021

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	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.010	T;T
MutationTaster	Benign	1.0	D;D;N;N
Sift4G	Pathogenic	0.0	D;D
Vest4		0.64
MVP		0.37
ClinPred		0.088	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142501705; hg19: chr19-45667499; COSMIC: COSV104524308; COSMIC: COSV104524308;