2-105272911-G-A

Variant names:

• chr2-105272911-G-A
• rs772581867
• NM_004257.6:c.1916C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004257.6(TGFBRAP1):​c.1916C>T​(p.Ala639Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,466 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. 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. A639G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TGFBRAP1 NM_004257.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.841
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05031374).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.1916C>T	p.Ala639Val	missense	Exon 10 of 12	NP_004248.2
	TGFBRAP1	NM_001142621.3		c.1916C>T	p.Ala639Val	missense	Exon 10 of 12	NP_001136093.1	Q8WUH2
	TGFBRAP1	NM_001328646.3		c.1916C>T	p.Ala639Val	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.1916C>T	p.Ala639Val	missense	Exon 10 of 12	ENSP00000377027.2	Q8WUH2
	TGFBRAP1	ENST00000595531.5	TSL:1	c.1916C>T	p.Ala639Val	missense	Exon 9 of 11	ENSP00000471434.2	Q8WUH2
	TGFBRAP1	ENST00000911279.1		c.1916C>T	p.Ala639Val	missense	Exon 10 of 12	ENSP00000581338.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458466 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725636

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50106

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111968

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	0.084
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.4
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.84
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.020
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.085
MutPred		0.28		Gain of methylation at K640 (P = 0.0511)
MVP		0.12
MPC		0.30
ClinPred		0.055	T
GERP RS		1.4
Varity_R		0.017
gMVP		0.099
Mutation Taster		=97/3	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: rs772581867; hg19: chr2-105889368;