2-105272917-G-C

Variant names:

• chr2-105272917-G-C
• rs150366059
• NM_004257.6:c.1910C>G

Variant summary

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

The NM_004257.6(TGFBRAP1):​c.1910C>G​(p.Thr637Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T637M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TGFBRAP1 NM_004257.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 publications found

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

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=0.1047664).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004257.6. 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
	TGFBRAP1	NM_004257.6	MANE Select	c.1910C>G	p.Thr637Arg	missense	Exon 10 of 12	NP_004248.2
	TGFBRAP1	NM_001142621.3		c.1910C>G	p.Thr637Arg	missense	Exon 10 of 12	NP_001136093.1	Q8WUH2
	TGFBRAP1	NM_001328646.3		c.1910C>G	p.Thr637Arg	missense	Exon 10 of 12	NP_001315575.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBRAP1	ENST00000393359.7	TSL:1 MANE Select	c.1910C>G	p.Thr637Arg	missense	Exon 10 of 12	ENSP00000377027.2	Q8WUH2
	TGFBRAP1	ENST00000595531.5	TSL:1	c.1910C>G	p.Thr637Arg	missense	Exon 9 of 11	ENSP00000471434.2	Q8WUH2
	TGFBRAP1	ENST00000911279.1		c.1910C>G	p.Thr637Arg	missense	Exon 10 of 12	ENSP00000581338.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458600 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725700

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.064
Sift	Benign	0.24	T
Sift4G	Uncertain	0.049	D
Polyphen		0.12	B
Vest4		0.39
MutPred		0.32		Gain of MoRF binding (P = 0.0148)
MVP		0.23
MPC		0.61
ClinPred		0.43	T
GERP RS		3.6
Varity_R		0.061
gMVP		0.49
Mutation Taster		=93/7	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: rs150366059; hg19: chr2-105889374;