4-183694013-T-C

Position:

• chr4-183694013-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021942.6(TRAPPC11):​c.2483T>C​(p.Val828Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00962 in 1,613,952 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (110 hom.)
• Consequence: TRAPPC11 NM_021942.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.02

Genes affected

TRAPPC11 (HGNC:25751): (trafficking protein particle complex subunit 11) The protein encoded by this gene is a subunit of the TRAPP (transport protein particle) tethering complex, which functions in intracellular vesicle trafficking. This subunit is involved in early stage endoplasmic reticulum-to-Golgi vesicle transport. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008762926).
• BP6: Variant 4-183694013-T-C is Benign according to our data. Variant chr4-183694013-T-C is described in ClinVar as [Benign]. Clinvar id is 261450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-183694013-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAPPC11	NM_021942.6	c.2483T>C	p.Val828Ala	missense_variant	22/30	ENST00000334690.11	NP_068761.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAPPC11	ENST00000334690.11	c.2483T>C	p.Val828Ala	missense_variant	22/30	1	NM_021942.6	ENSP00000335371	P1
TRAPPC11	ENST00000357207.8	c.2483T>C	p.Val828Ala	missense_variant	22/31	1		ENSP00000349738
TRAPPC11	ENST00000512476.1	c.1301T>C	p.Val434Ala	missense_variant	11/19	1		ENSP00000421004
TRAPPC11	ENST00000505676.5	c.*597T>C		3_prime_UTR_variant, NMD_transcript_variant	10/19	1		ENSP00000422915

Frequencies

GnomAD3 genomes AF: 0.00771 AC: 1174 AN: 152222 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00797 AC: 2003 AN: 251238 Hom.: 18 AF XY: 0.00828 AC XY: 1124 AN XY: 135766

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00526

Gnomad FIN exome AF: 0.00956

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00982 AC: 14349 AN: 1461612 Hom.: 110 Cov.: 32 AF XY: 0.00991 AC XY: 7204 AN XY: 727072

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00543

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00660

Gnomad4 FIN exome AF: 0.00859

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00956

GnomAD4 genome AF: 0.00771 AC: 1174 AN: 152340 Hom.: 9 Cov.: 33 AF XY: 0.00781 AC XY: 582 AN XY: 74496

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00995 Hom.: 14

Bravo AF: 0.00716

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0112 AC: 96

ExAC AF: 0.00834 AC: 1013

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TRAPPC11: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive limb-girdle muscular dystrophy type R18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
MetaRNN	Benign	0.0088	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.076
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.11	T;T;D
Polyphen		0.17	B;B;P
Vest4		0.56
MVP		0.44
MPC		0.31
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.077
gMVP		0.48

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: rs75176151; hg19: chr4-184615166;