chr2-105269692-T-G

Variant names:

• chr2-105269692-T-G
• rs144071743
• NM_004257.6:c.1986A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004257.6(TGFBRAP1):​c.1986A>C​(p.Gly662Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00763 in 1,546,164 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (60 hom.)
• Consequence: TGFBRAP1 NM_004257.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0690
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-105269692-T-G is Benign according to our data. Variant chr2-105269692-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2651227.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.069 with no splicing effect.
• BS2: High AC in GnomAd4 at 804 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.1986A>C	p.Gly662Gly	synonymous	Exon 11 of 12	NP_004248.2
	TGFBRAP1	NM_001142621.3		c.1986A>C	p.Gly662Gly	synonymous	Exon 11 of 12	NP_001136093.1	Q8WUH2
	TGFBRAP1	NM_001328646.3		c.1986A>C	p.Gly662Gly	synonymous	Exon 11 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.1986A>C	p.Gly662Gly	synonymous	Exon 11 of 12	ENSP00000377027.2	Q8WUH2
	TGFBRAP1	ENST00000595531.5	TSL:1	c.1986A>C	p.Gly662Gly	synonymous	Exon 10 of 11	ENSP00000471434.2	Q8WUH2
	TGFBRAP1	ENST00000911279.1		c.2067A>C	p.Gly689Gly	synonymous	Exon 11 of 12	ENSP00000581338.1

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 804 AN: 152092 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00592 AC: 1189 AN: 200906 AF XY: 0.00606

Gnomad AFR exome AF: 0.00159

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00389

Gnomad NFE exome AF: 0.00972

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00788 AC: 10986 AN: 1393954 Hom.: 60 Cov.: 34 AF XY: 0.00782 AC XY: 5350 AN XY: 684100

African (AFR) AF: 0.00124 AC: 40 AN: 32208

American (AMR) AF: 0.00175 AC: 70 AN: 40106

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 40 AN: 22366

East Asian (EAS) AF: 0.00 AC: 0 AN: 38802

South Asian (SAS) AF: 0.00445 AC: 343 AN: 77150

European-Finnish (FIN) AF: 0.00409 AC: 185 AN: 45280

Middle Eastern (MID) AF: 0.00293 AC: 15 AN: 5122

European-Non Finnish (NFE) AF: 0.00925 AC: 9943 AN: 1075348

Other (OTH) AF: 0.00608 AC: 350 AN: 57572

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152210 Hom.: 1 Cov.: 32 AF XY: 0.00485 AC XY: 361 AN XY: 74438

African (AFR) AF: 0.00183 AC: 76 AN: 41532

American (AMR) AF: 0.00229 AC: 35 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4830

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00906 AC: 616 AN: 67992

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00611 Hom.: 3

Bravo AF: 0.00512

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.040
DANN	Benign	0.33
PhyloP100		-0.069
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs144071743; hg19: chr2-105886149; COSMIC: COSV99305412;