rs764083534

Variant names:

• chr4-183677502-A-G
• rs764083534
• NM_021942.6:c.779A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-183677502-A-G
• chr4-183677502-A-T

Variant summary

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

The NM_021942.6(TRAPPC11):​c.779A>G​(p.His260Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,609,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H260D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TRAPPC11 NM_021942.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.06
• 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: Orphanet, Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• 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: Very rare variant in population databases, with high coverage

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.779A>G	p.His260Arg	missense	Exon 8 of 30	NP_068761.4
	TRAPPC11	NM_199053.3		c.779A>G	p.His260Arg	missense	Exon 8 of 31	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.779A>G	p.His260Arg	missense	Exon 8 of 30	ENSP00000335371.6	Q7Z392-1
	TRAPPC11	ENST00000357207.8	TSL:1	c.779A>G	p.His260Arg	missense	Exon 8 of 31	ENSP00000349738.4	Q7Z392-3
	TRAPPC11	ENST00000505676.5	TSL:1	n.163-2706A>G		intron	N/A	ENSP00000422915.1	D6R9T9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250870 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1457074 Hom.: 0 Cov.: 28 AF XY: 0.00000414 AC XY: 3 AN XY: 725204

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.000179 AC: 8 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1108002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60230

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74398

African (AFR) AF: 0.00 AC: 0 AN: 41480

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type R18 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0069	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.53
Sift	Benign	0.22	T
Sift4G	Benign	0.38	T
Polyphen		0.91	P
Vest4		0.79
MutPred		0.37		Gain of solvent accessibility (P = 0.039)
MVP		0.65
MPC		0.31
ClinPred		0.54	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.37
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs764083534; hg19: chr4-184598655;