rs4669

Variant names:

• chr5-136056737-T-C
• rs4669
• NM_000358.3:c.1620T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-136056737-T-C
• chr5-136056737-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000358.3(TGFBI):​c.1620T>C​(p.Phe540Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,613,520 control chromosomes in the GnomAD database, including 77,797 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12807 hom., cov: 31)
  • Exomes 𝑓: 0.29 (64990 hom.)
• Consequence: TGFBI NM_000358.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.359

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=-0.359 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.1620T>C	p.Phe540Phe	synonymous_variant	Exon 12 of 17	ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.1620T>C	p.Phe540Phe	synonymous_variant	Exon 12 of 17	1	NM_000358.3	ENSP00000416330.2

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57714 AN: 151768 Hom.: 12766 Cov.: 31

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.326 AC: 81231 AN: 248942 Hom.: 14356 AF XY: 0.320 AC XY: 43184 AN XY: 135060

Gnomad AFR exome AF: 0.633

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.322

Gnomad SAS exome AF: 0.371

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.291 AC: 425210 AN: 1461634 Hom.: 64990 Cov.: 36 AF XY: 0.291 AC XY: 211950 AN XY: 727108

Gnomad4 AFR exome AF: 0.639

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.370

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.381 AC: 57823 AN: 151886 Hom.: 12807 Cov.: 31 AF XY: 0.379 AC XY: 28122 AN XY: 74232

Gnomad4 AFR AF: 0.622

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.365

Alfa AF: 0.289 Hom.: 13797

Bravo AF: 0.396

Asia WGS AF: 0.373 AC: 1296 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.257

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Corneal dystrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.7
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs4669; hg19: chr5-135392426; COSMIC: COSV59351022; COSMIC: COSV59351022;