NM_021942.6:c.-21-92delT

Variant names:

• chr4-183663736-GT-G
• rs70959134
• NM_021942.6:c.-21-92delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_021942.6(TRAPPC11):​c.-21-92delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 386,590 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 0.0039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.022 (0 hom.)
• Consequence: TRAPPC11 NM_021942.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.751
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0417) population. However there is too low homozygotes in high coverage region: (expected more than 28, got 0).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00387 (418/108042) while in subpopulation SAS AF = 0.00867 (28/3228). AF 95% confidence interval is 0.0068. There are 0 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.-21-92delT		intron	N/A	NP_068761.4
	TRAPPC11	NM_199053.3		c.-21-92delT		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.-21-110delT		intron	N/A	ENSP00000335371.6	Q7Z392-1
	TRAPPC11	ENST00000357207.8	TSL:1	c.-21-110delT		intron	N/A	ENSP00000349738.4	Q7Z392-3
	TRAPPC11	ENST00000505676.5	TSL:1	n.-21-110delT		intron	N/A	ENSP00000422915.1	D6R9T9

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 417 AN: 108050 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00759

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.000706

Gnomad EAS AF: 0.00610

Gnomad SAS AF: 0.00866

Gnomad FIN AF: 0.00150

Gnomad MID AF: 0.00463

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00546

GnomAD4 exome AF: 0.0222 AC: 6193 AN: 278548 Hom.: 0 AF XY: 0.0229 AC XY: 3356 AN XY: 146246

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

African (AFR) AF: 0.0256 AC: 181 AN: 7062

American (AMR) AF: 0.0364 AC: 401 AN: 11024

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 104 AN: 8170

East Asian (EAS) AF: 0.0185 AC: 328 AN: 17762

South Asian (SAS) AF: 0.0438 AC: 1174 AN: 26794

European-Finnish (FIN) AF: 0.0144 AC: 292 AN: 20306

Middle Eastern (MID) AF: 0.0182 AC: 21 AN: 1156

European-Non Finnish (NFE) AF: 0.0199 AC: 3389 AN: 170450

Other (OTH) AF: 0.0191 AC: 303 AN: 15824

⚠️ 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: 0.00387 AC: 418 AN: 108042 Hom.: 0 Cov.: 0 AF XY: 0.00396 AC XY: 202 AN XY: 51064

African (AFR) AF: 0.00762 AC: 225 AN: 29532

American (AMR) AF: 0.00387 AC: 41 AN: 10602

Ashkenazi Jewish (ASJ) AF: 0.000706 AC: 2 AN: 2834

East Asian (EAS) AF: 0.00613 AC: 21 AN: 3426

South Asian (SAS) AF: 0.00867 AC: 28 AN: 3228

European-Finnish (FIN) AF: 0.00150 AC: 7 AN: 4682

Middle Eastern (MID) AF: 0.00510 AC: 1 AN: 196

European-Non Finnish (NFE) AF: 0.00166 AC: 85 AN: 51300

Other (OTH) AF: 0.00544 AC: 8 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		-0.75
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: rs70959134; hg19: chr4-184584889; COSMIC: COSV58217458; COSMIC: COSV58217458;