chr4-183663736-G-GTTTT

Variant names:

• chr4-183663736-G-GTTTT
• rs70959134
• NM_021942.6:c.-21-95_-21-92dupTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_021942.6(TRAPPC11):​c.-21-95_-21-92dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000479 in 388,274 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00061 (4 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000614 (172/280254) while in subpopulation AFR AF = 0.00196 (14/7134). AF 95% confidence interval is 0.00119. There are 4 homozygotes in GnomAdExome4. There are 103 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.-21-95_-21-92dupTTTT		intron	N/A	NP_068761.4
	TRAPPC11	NM_199053.3		c.-21-95_-21-92dupTTTT		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.-21-111_-21-110insTTTT		intron	N/A	ENSP00000335371.6	Q7Z392-1
	TRAPPC11	ENST00000357207.8	TSL:1	c.-21-111_-21-110insTTTT		intron	N/A	ENSP00000349738.4	Q7Z392-3
	TRAPPC11	ENST00000505676.5	TSL:1	n.-21-111_-21-110insTTTT		intron	N/A	ENSP00000422915.1	D6R9T9

Frequencies

GnomAD3 genomes AF: 0.000130 AC: 14 AN: 108028 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000944

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: 0.0000975

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000614 AC: 172 AN: 280254 Hom.: 4 AF XY: 0.000700 AC XY: 103 AN XY: 147218

African (AFR) AF: 0.00196 AC: 14 AN: 7134

American (AMR) AF: 0.000807 AC: 9 AN: 11158

Ashkenazi Jewish (ASJ) AF: 0.000488 AC: 4 AN: 8200

East Asian (EAS) AF: 0.000280 AC: 5 AN: 17882

South Asian (SAS) AF: 0.00140 AC: 38 AN: 27102

European-Finnish (FIN) AF: 0.000246 AC: 5 AN: 20358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1156

European-Non Finnish (NFE) AF: 0.000525 AC: 90 AN: 171378

Other (OTH) AF: 0.000441 AC: 7 AN: 15886

GnomAD4 genome AF: 0.000130 AC: 14 AN: 108020 Hom.: 0 Cov.: 0 AF XY: 0.000118 AC XY: 6 AN XY: 51062

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

African (AFR) AF: 0.000271 AC: 8 AN: 29520

American (AMR) AF: 0.0000943 AC: 1 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: 0.00 AC: 0 AN: 3228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4686

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

European-Non Finnish (NFE) AF: 0.0000975 AC: 5 AN: 51290

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs70959134; hg19: chr4-184584889;