rs41298960

chr5-136046835-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000358.3(TGFBI):c.460-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,608,954 control chromosomes in the GnomAD database, including 3,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (211 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3423 hom.)
• Consequence: TGFBI NM_000358.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0800

Genes affected

TGFBI (HGNC:11771): (transforming growth factor beta induced) This gene encodes an RGD-containing protein that binds to type I, II and IV collagens. The RGD motif is found in many extracellular matrix proteins modulating cell adhesion and serves as a ligand recognition sequence for several integrins. This protein plays a role in cell-collagen interactions and may be involved in endochondrial bone formation in cartilage. The protein is induced by transforming growth factor-beta and acts to inhibit cell adhesion. Mutations in this gene are associated with multiple types of corneal dystrophy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBI	NM_000358.3	c.460-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000442011.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBI	ENST00000442011.7	c.460-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000358.3	P1
TGFBI	ENST00000506699.5	n.864C>T		non_coding_transcript_exon_variant	4/17	2
TGFBI	ENST00000515433.1	n.1091C>T		non_coding_transcript_exon_variant	1/4	2
TGFBI	ENST00000507018.5	c.*53-16C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6981 AN: 152028 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0449

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.0479

GnomAD3 exomes AF: 0.0474 AC: 11600 AN: 244570 Hom.: 359 AF XY: 0.0495 AC XY: 6561 AN XY: 132594

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.0235

Gnomad ASJ exome AF: 0.0499

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0322

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0700

Gnomad OTH exome AF: 0.0518

GnomAD4 exome AF: 0.0651 AC: 94777 AN: 1456808 Hom.: 3423 Cov.: 31 AF XY: 0.0643 AC XY: 46547 AN XY: 724166

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.0257

Gnomad4 ASJ exome AF: 0.0467

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0348

Gnomad4 FIN exome AF: 0.0552

Gnomad4 NFE exome AF: 0.0746

Gnomad4 OTH exome AF: 0.0545

GnomAD4 genome AF: 0.0459 AC: 6979 AN: 152146 Hom.: 211 Cov.: 32 AF XY: 0.0440 AC XY: 3274 AN XY: 74382

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0363

Gnomad4 ASJ AF: 0.0449

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0517

Gnomad4 NFE AF: 0.0722

Gnomad4 OTH AF: 0.0469

Alfa AF: 0.0562 Hom.: 57

Bravo AF: 0.0439

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.9
Dann	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs41298960; hg19: chr5-135382524;