rs151021715

Positions:

• chr4-183693918-A-C
• chr4-183693918-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_021942.6(TRAPPC11):​c.2388A>C​(p.Gly796=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,613,410 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G796G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: TRAPPC11 NM_021942.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003657
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.07

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 4-183693918-A-C is Benign according to our data. Variant chr4-183693918-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261447.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC11	NM_021942.6	c.2388A>C	p.Gly796=	splice_region_variant, synonymous_variant	22/30	ENST00000334690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC11	ENST00000334690.11	c.2388A>C	p.Gly796=	splice_region_variant, synonymous_variant	22/30	1	NM_021942.6	P1
TRAPPC11	ENST00000357207.8	c.2388A>C	p.Gly796=	splice_region_variant, synonymous_variant	22/31	1
TRAPPC11	ENST00000512476.1	c.1206A>C	p.Gly402=	splice_region_variant, synonymous_variant	11/19	1
TRAPPC11	ENST00000505676.5	c.*502A>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	10/19	1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00149 AC: 373 AN: 251094 Hom.: 0 AF XY: 0.00150 AC XY: 203 AN XY: 135690

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00188 AC: 2740 AN: 1461088 Hom.: 2 Cov.: 32 AF XY: 0.00179 AC XY: 1299 AN XY: 726696

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00121 AC XY: 90 AN XY: 74488

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00129

EpiCase AF: 0.00202

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2024	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TRAPPC11: BP4, BP7 -

Autosomal recessive limb-girdle muscular dystrophy type R18 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jul 13, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.016
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: rs151021715; hg19: chr4-184615071;