chr1-47775182-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001194986.2(TRABD2B):​c.1337G>A​(p.Arg446His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,235,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TRABD2B
NM_001194986.2 missense

Scores

6
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.47
Variant links:
Genes affected
TRABD2B (HGNC:44200): (TraB domain containing 2B) Enables Wnt-protein binding activity and metalloendopeptidase activity. Involved in several processes, including negative regulation of Wnt signaling pathway; positive regulation of protein oxidation; and positive regulation of protein-containing complex assembly. Is integral component of organelle membrane and integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRABD2BNM_001194986.2 linkc.1337G>A p.Arg446His missense_variant Exon 6 of 7 ENST00000606738.3 NP_001181915.1 A6NFA1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRABD2BENST00000606738.3 linkc.1337G>A p.Arg446His missense_variant Exon 6 of 7 1 NM_001194986.2 ENSP00000476820.1 A6NFA1
TRABD2BENST00000435576.2 linkn.*56G>A downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000110
AC:
1
AN:
9128
Hom.:
0
AF XY:
0.000225
AC XY:
1
AN XY:
4436
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00463
GnomAD4 exome
AF:
0.0000111
AC:
12
AN:
1083422
Hom.:
0
Cov.:
31
AF XY:
0.00000781
AC XY:
4
AN XY:
512032
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000375
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000109
Gnomad4 OTH exome
AF:
0.0000228
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1337G>A (p.R446H) alteration is located in exon 6 (coding exon 6) of the TRABD2B gene. This alteration results from a G to A substitution at nucleotide position 1337, causing the arginine (R) at amino acid position 446 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.031
T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.84
T
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.0
M
PrimateAI
Uncertain
0.72
T
Sift4G
Uncertain
0.0040
D
Vest4
0.71
MVP
0.25
MPC
2.1
GERP RS
5.7
Varity_R
0.16
gMVP
0.46

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs919659872; hg19: chr1-48240854; API