4-183663736-GTTTTTTTT-GTTTTTT

Variant names:

• chr4-183663736-GTT-G
• rs70959134
• NM_021942.6:c.-21-93_-21-92delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021942.6(TRAPPC11):​c.-21-93_-21-92delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 384,364 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0074 (0 hom.)
• Consequence: TRAPPC11 NM_021942.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.972
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0138) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021942.6. 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.-21-93_-21-92delTT		intron	N/A	NP_068761.4
	TRAPPC11	NM_199053.3		c.-21-93_-21-92delTT		intron	N/A	NP_951008.1	Q7Z392-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC11	ENST00000334690.11	TSL:1 MANE Select	c.-21-110_-21-109delTT		intron	N/A	ENSP00000335371.6	Q7Z392-1
	TRAPPC11	ENST00000357207.8	TSL:1	c.-21-110_-21-109delTT		intron	N/A	ENSP00000349738.4	Q7Z392-3
	TRAPPC11	ENST00000505676.5	TSL:1	n.-21-110_-21-109delTT		intron	N/A	ENSP00000422915.1	D6R9T9

Frequencies

GnomAD3 genomes AF: 0.0000740 AC: 8 AN: 108050 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000390

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00741 AC: 2047 AN: 276322 Hom.: 0 AF XY: 0.00763 AC XY: 1108 AN XY: 145132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00994 AC: 70 AN: 7044

American (AMR) AF: 0.0133 AC: 145 AN: 10874

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 42 AN: 8128

East Asian (EAS) AF: 0.00602 AC: 106 AN: 17622

South Asian (SAS) AF: 0.0150 AC: 396 AN: 26330

European-Finnish (FIN) AF: 0.00357 AC: 72 AN: 20190

Middle Eastern (MID) AF: 0.00175 AC: 2 AN: 1140

European-Non Finnish (NFE) AF: 0.00661 AC: 1119 AN: 169282

Other (OTH) AF: 0.00605 AC: 95 AN: 15712

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000648 AC: 7 AN: 108042 Hom.: 0 Cov.: 0 AF XY: 0.0000783 AC XY: 4 AN XY: 51060

African (AFR) AF: 0.0000339 AC: 1 AN: 29536

American (AMR) AF: 0.00 AC: 0 AN: 10600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2834

East Asian (EAS) AF: 0.00 AC: 0 AN: 3426

South Asian (SAS) AF: 0.000929 AC: 3 AN: 3228

European-Finnish (FIN) AF: 0.000214 AC: 1 AN: 4678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.0000390 AC: 2 AN: 51302

Other (OTH) AF: 0.00 AC: 0 AN: 1470

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97

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: rs70959134; hg19: chr4-184584889;