chr2-105273588-G-A

Position:

• chr2-105273588-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004257.6(TGFBRAP1):​c.1768C>T​(p.Leu590Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TGFBRAP1 NM_004257.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

TGFBRAP1 (HGNC:16836): (transforming growth factor beta receptor associated protein 1) This gene encodes a protein that binds to transforming growth factor-beta (TGF-beta) receptors and plays a role in TGF-beta signaling. The encoded protein acts as a chaprone in signaling downstream of TGF-beta. It is involved in signal-dependent association with SMAD4. The protein is also a component of mammalian CORVET, a multisubunit tethering protein complex that is involved in fusion of early endosomes. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBRAP1	NM_004257.6	c.1768C>T	p.Leu590Phe	missense_variant	9/12	ENST00000393359.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBRAP1	ENST00000393359.7	c.1768C>T	p.Leu590Phe	missense_variant	9/12	1	NM_004257.6	P1
TGFBRAP1	ENST00000595531.5	c.1768C>T	p.Leu590Phe	missense_variant	8/11	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.1768C>T (p.L590F) alteration is located in exon 9 (coding exon 8) of the TGFBRAP1 gene. This alteration results from a C to T substitution at nucleotide position 1768, causing the leucine (L) at amino acid position 590 to be replaced by a phenylalanine (F). 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	Benign	0.21
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;.;.
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	.;D;D
REVEL	Benign	0.23
Sift	Benign	0.065	.;T;T
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.79	P;P;P
Vest4		0.48
MutPred		0.58		Gain of methylation at K585 (P = 0.0585);Gain of methylation at K585 (P = 0.0585);Gain of methylation at K585 (P = 0.0585);
MVP		0.76
MPC		0.94
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.31

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-105890045;