chr2-105267517-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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
• 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: Likely_benign. The variant received -2 ACMG points.

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

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.2449C>G	p.Leu817Val	missense	Exon 12 of 12	NP_004248.2
	TGFBRAP1	NM_001142621.3		c.2449C>G	p.Leu817Val	missense	Exon 12 of 12	NP_001136093.1	Q8WUH2
	TGFBRAP1	NM_001328646.3		c.2406+1755C>G		intron	N/A	NP_001315575.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBRAP1	ENST00000393359.7	TSL:1 MANE Select	c.2449C>G	p.Leu817Val	missense	Exon 12 of 12	ENSP00000377027.2	Q8WUH2
	TGFBRAP1	ENST00000595531.5	TSL:1	c.2449C>G	p.Leu817Val	missense	Exon 11 of 11	ENSP00000471434.2	Q8WUH2
	TGFBRAP1	ENST00000911279.1		c.2530C>G	p.Leu844Val	missense	Exon 12 of 12	ENSP00000581338.1

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

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.11
DEOGEN2	Benign	0.11	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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.047
Sift	Benign	0.84	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.34		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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1412039218; hg19: chr2-105883974;