chr1-47775182-C-T

Variant names:

• chr1-47775182-C-T
• rs919659872
• NM_001194986.2:c.1337G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194986.2. 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
	TRABD2B	NM_001194986.2	MANE Select	c.1337G>A	p.Arg446His	missense	Exon 6 of 7	NP_001181915.1	A6NFA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRABD2B	ENST00000606738.3	TSL:1 MANE Select	c.1337G>A	p.Arg446His	missense	Exon 6 of 7	ENSP00000476820.1	A6NFA1
	TRABD2B	ENST00000878673.1		c.1442G>A	p.Arg481His	missense	Exon 7 of 8	ENSP00000548732.1
	TRABD2B	ENST00000878672.1		c.1190G>A	p.Arg397His	missense	Exon 5 of 6	ENSP00000548731.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000110 AC: 1 AN: 9128 AF XY: 0.000225

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 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

African (AFR) AF: 0.00 AC: 0 AN: 23052

American (AMR) AF: 0.00 AC: 0 AN: 8652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14460

East Asian (EAS) AF: 0.0000375 AC: 1 AN: 26654

South Asian (SAS) AF: 0.00 AC: 0 AN: 20702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2930

European-Non Finnish (NFE) AF: 0.0000109 AC: 10 AN: 921350

Other (OTH) AF: 0.0000228 AC: 1 AN: 43862

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74484

African (AFR) AF: 0.0000722 AC: 3 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.5
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
Mutation Taster		=43/57	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: rs919659872; hg19: chr1-48240854;