4-183693144-C-T

Variant names:

• chr4-183693144-C-T
• rs768000138
• NM_021942.6:c.2234C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021942.6(TRAPPC11):​c.2234C>T​(p.Thr745Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,431,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRAPPC11 NM_021942.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC11	NM_021942.6	c.2234C>T	p.Thr745Ile	missense_variant	Exon 20 of 30	ENST00000334690.11	NP_068761.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC11	ENST00000334690.11	c.2234C>T	p.Thr745Ile	missense_variant	Exon 20 of 30	1	NM_021942.6	ENSP00000335371.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1431396 Hom.: 0 Cov.: 30 AF XY: 0.00000423 AC XY: 3 AN XY: 708628

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 06, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;D;N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.77	P;P;D
Vest4		0.88
MutPred		0.48		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;
MVP		0.37
MPC		0.72
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.29
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs768000138; hg19: chr4-184614297; COSMIC: COSV100591703;