1-47775377-G-A

Variant names:

• chr1-47775377-G-A
• rs1235986922
• NM_001194986.2:c.1142C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001194986.2(TRABD2B):​c.1142C>T​(p.Thr381Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000921 in 1,085,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: TRABD2B NM_001194986.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17600253).

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.1142C>T	p.Thr381Ile	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.1142C>T	p.Thr381Ile	missense	Exon 6 of 7	ENSP00000476820.1	A6NFA1
	TRABD2B	ENST00000878673.1		c.1247C>T	p.Thr416Ile	missense	Exon 7 of 8	ENSP00000548732.1
	TRABD2B	ENST00000878672.1		c.995C>T	p.Thr332Ile	missense	Exon 5 of 6	ENSP00000548731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1085502 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 513278

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

African (AFR) AF: 0.00 AC: 0 AN: 23126

American (AMR) AF: 0.00 AC: 0 AN: 8638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14470

East Asian (EAS) AF: 0.00 AC: 0 AN: 26612

South Asian (SAS) AF: 0.00 AC: 0 AN: 21060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 921704

Other (OTH) AF: 0.0000227 AC: 1 AN: 43970

⚠️ 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 Cov.: 33

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	Benign	0.092
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.0027	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.18	T
MutationAssessor	Benign	0.69	N
PhyloP100		6.3
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.41	T
Vest4		0.12
MVP		0.16
MPC		1.0
GERP RS		5.1
Varity_R		0.063
gMVP		0.24
Mutation Taster		=89/11	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: rs1235986922; hg19: chr1-48241049;