2-105267517-G-C

Variant names:

• chr2-105267517-G-C
• rs1412039218
• NM_004257.6:c.2449C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004257.6(TGFBRAP1):​c.2449C>G​(p.Leu817Val) 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 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TGFBRAP1 NM_004257.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051531494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBRAP1	NM_004257.6	c.2449C>G	p.Leu817Val	missense_variant	Exon 12 of 12	ENST00000393359.7	NP_004248.2
TGFBRAP1	NM_001142621.3	c.2449C>G	p.Leu817Val	missense_variant	Exon 12 of 12		NP_001136093.1
TGFBRAP1	NM_001426428.1	c.2449C>G	p.Leu817Val	missense_variant	Exon 12 of 13		NP_001413357.1
TGFBRAP1	NM_001328646.3	c.2406+1755C>G		intron_variant	Intron 11 of 11		NP_001315575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBRAP1	ENST00000393359.7	c.2449C>G	p.Leu817Val	missense_variant	Exon 12 of 12	1	NM_004257.6	ENSP00000377027.2
TGFBRAP1	ENST00000595531.5	c.2449C>G	p.Leu817Val	missense_variant	Exon 11 of 11	1		ENSP00000471434.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2449C>G (p.L817V) alteration is located in exon 12 (coding exon 11) of the TGFBRAP1 gene. This alteration results from a C to G substitution at nucleotide position 2449, causing the leucine (L) at amino acid position 817 to be replaced by a valine (V). 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	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.11
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.0098
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.71	T;.;.
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.24	.;N;N
REVEL	Benign	0.047
Sift	Benign	0.84	.;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.042
MutPred		0.34		Gain of methylation at K816 (P = 0.0598);Gain of methylation at K816 (P = 0.0598);Gain of methylation at K816 (P = 0.0598);
MVP		0.44
MPC		0.30
ClinPred		0.18	T
GERP RS		5.5
Varity_R		0.035
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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

Other links and lift over

dbSNP: rs1412039218; hg19: chr2-105883974;