rs41298960

Variant names:

• chr5-136046835-C-T
• rs41298960
• NM_000358.3:c.460-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000358.3(TGFBI):​c.460-16C>T variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0800
• Publications: 4 publications found

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]

TGFBI Gene-Disease associations (from GenCC):

• epithelial-stromal TGFBI dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia
• granular corneal dystrophy type I

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• granular corneal dystrophy type II

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• lattice corneal dystrophy type I

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Reis-Bucklers corneal dystrophy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Thiel-Behnke corneal dystrophy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• epithelial basement membrane dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-136046835-C-T is Benign according to our data. Variant chr5-136046835-C-T is described in ClinVar as Benign. ClinVar VariationId is 255938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000358.3. 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
	TGFBI	NM_000358.3	MANE Select	c.460-16C>T		intron	N/A	NP_000349.1	Q15582

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBI	ENST00000442011.7	TSL:1 MANE Select	c.460-16C>T		intron	N/A	ENSP00000416330.2	Q15582
	TGFBI	ENST00000506699.5	TSL:2	n.864C>T		non_coding_transcript_exon	Exon 4 of 17
	TGFBI	ENST00000515433.1	TSL:2	n.1091C>T		non_coding_transcript_exon	Exon 1 of 4

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

GnomAD2 exomes AF: 0.0474 AC: 11600 AN: 244570 AF XY: 0.0495

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 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

African (AFR) AF: 0.0109 AC: 364 AN: 33432

American (AMR) AF: 0.0257 AC: 1145 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 1204 AN: 25754

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39612

South Asian (SAS) AF: 0.0348 AC: 2981 AN: 85588

European-Finnish (FIN) AF: 0.0552 AC: 2932 AN: 53154

Middle Eastern (MID) AF: 0.0252 AC: 144 AN: 5714

European-Non Finnish (NFE) AF: 0.0746 AC: 82720 AN: 1108842

Other (OTH) AF: 0.0545 AC: 3280 AN: 60210

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

African (AFR) AF: 0.0124 AC: 515 AN: 41530

American (AMR) AF: 0.0363 AC: 555 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0449 AC: 156 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5142

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4818

European-Finnish (FIN) AF: 0.0517 AC: 548 AN: 10602

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0722 AC: 4907 AN: 67970

Other (OTH) AF: 0.0469 AC: 99 AN: 2110

Alfa AF: 0.0483 Hom.: 133

Bravo AF: 0.0439

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.46
PhyloP100		0.080
PromoterAI		-0.0092	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs41298960; hg19: chr5-135382524;