NM_001270891.2:c.394T>C

Variant names:

• chr19-45163970-A-G
• rs774235826
• NM_001270891.2:c.394T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001270891.2(TRAPPC6A):​c.394T>C​(p.Tyr132His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. 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. Y132N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TRAPPC6A NM_001270891.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.972
• Publications: 0 publications found

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]

MARK4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055158705).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270891.2. 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
	TRAPPC6A	NM_001270891.2	MANE Select	c.394T>C	p.Tyr132His	missense	Exon 5 of 6	NP_001257820.1	O75865-1
	TRAPPC6A	NM_024108.3		c.436T>C	p.Tyr146His	missense	Exon 5 of 6	NP_077013.1	O75865-2
	TRAPPC6A	NM_001270892.2		c.368T>C	p.Leu123Pro	missense	Exon 4 of 5	NP_001257821.1	O75865-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC6A	ENST00000585934.1	TSL:1 MANE Select	c.394T>C	p.Tyr132His	missense	Exon 5 of 6	ENSP00000468612.1	O75865-1
	TRAPPC6A	ENST00000006275.8	TSL:1	c.436T>C	p.Tyr146His	missense	Exon 5 of 6	ENSP00000006275.3	O75865-2
	TRAPPC6A	ENST00000940426.1		c.352T>C	p.Tyr118His	missense	Exon 4 of 5	ENSP00000610485.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429336 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 707568

African (AFR) AF: 0.00 AC: 0 AN: 33230

American (AMR) AF: 0.00 AC: 0 AN: 38300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 38638

South Asian (SAS) AF: 0.00 AC: 0 AN: 81312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096248

Other (OTH) AF: 0.00 AC: 0 AN: 59328

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.3
DANN	Benign	0.88
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.055	T
PhyloP100		-0.97
Vest4		0.090
MVP		0.067
ClinPred		0.17	T
GERP RS		-0.28
Varity_R		0.16
Mutation Taster		=86/14	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: rs774235826; hg19: chr19-45667228;