NM_000358.3:c.233+3G>A

Variant names:

• chr5-136033864-G-A
• rs375152141
• NM_000358.3:c.233+3G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000358.3(TGFBI):​c.233+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,612,800 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: TGFBI NM_000358.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002301
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.11
• Publications: 0 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 Submitted by: Ambry Genetics
• 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: Orphanet, G2P
• Thiel-Behnke corneal dystrophy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-136033864-G-A is Benign according to our data. Variant chr5-136033864-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1645832.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.233+3G>A		splice_region_variant, intron_variant	Intron 2 of 16	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.233+3G>A		splice_region_variant, intron_variant	Intron 2 of 16	1	NM_000358.3	ENSP00000416330.2
TGFBI	ENST00000504185.5	n.301+3G>A		splice_region_variant, intron_variant	Intron 2 of 4	4
TGFBI	ENST00000506699.5	n.298+3G>A		splice_region_variant, intron_variant	Intron 2 of 16	2
TGFBI	ENST00000507018.5	n.149+3G>A		splice_region_variant, intron_variant	Intron 2 of 16	5		ENSP00000421540.1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000174 AC: 43 AN: 247754 AF XY: 0.000112

Gnomad AFR exome AF: 0.00254

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1460454 Hom.: 0 Cov.: 29 AF XY: 0.0000468 AC XY: 34 AN XY: 726434

African (AFR) AF: 0.00191 AC: 64 AN: 33464

American (AMR) AF: 0.0000448 AC: 2 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111160

Other (OTH) AF: 0.000116 AC: 7 AN: 60334

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.000617 AC XY: 46 AN XY: 74514

African (AFR) AF: 0.00267 AC: 111 AN: 41568

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000888 Hom.: 1

Bravo AF: 0.000669

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.66
PhyloP100		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0060
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: rs375152141; hg19: chr5-135369553;