4-183694726-AT-A

Variant names:

• chr4-183694726-AT-A
• rs150593522
• NM_021942.6:c.2628+10delT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The ENST00000334690.11(TRAPPC11):​c.2628+4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,603,446 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: TRAPPC11 ENST00000334690.11 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.713
• Publications: 0 publications found

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]

TRAPPC11 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type R18

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Orphanet
• intellectual disability-hyperkinetic movement-truncal ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• triple-A syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 4-183694726-AT-A is Benign according to our data. Variant chr4-183694726-AT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474351.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00112 (1622/1451268) while in subpopulation NFE AF = 0.00142 (1576/1109624). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAdExome4. There are 759 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000334690.11. 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
	TRAPPC11	NM_021942.6	MANE Select	c.2628+10delT		intron	N/A	NP_068761.4
	TRAPPC11	NM_199053.3		c.2628+10delT		intron	N/A	NP_951008.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC11	ENST00000334690.11	TSL:1 MANE Select	c.2628+4delT		splice_region intron	N/A	ENSP00000335371.6
	TRAPPC11	ENST00000357207.8	TSL:1	c.2628+4delT		splice_region intron	N/A	ENSP00000349738.4
	TRAPPC11	ENST00000512476.1	TSL:1	c.1446+4delT		splice_region intron	N/A	ENSP00000421004.1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000453 AC: 108 AN: 238294 AF XY: 0.000427

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.0000652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000924

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.00112 AC: 1622 AN: 1451268 Hom.: 0 Cov.: 30 AF XY: 0.00105 AC XY: 759 AN XY: 721564

African (AFR) AF: 0.000184 AC: 6 AN: 32642

American (AMR) AF: 0.0000725 AC: 3 AN: 41398

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 83094

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00142 AC: 1576 AN: 1109624

Other (OTH) AF: 0.000500 AC: 30 AN: 59990

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74418

African (AFR) AF: 0.000241 AC: 10 AN: 41516

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000927 AC: 63 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000111 Hom.: 1

Bravo AF: 0.000423

EpiCase AF: 0.000875

EpiControl AF: 0.000954

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type R18 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
Mutation Taster		=100/0	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: rs150593522; hg19: chr4-184615879; COSMIC: COSV58216891;