rs2072239

Positions:

• chr5-136056818-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_000358.3(TGFBI):​c.1678+23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,597,300 control chromosomes in the GnomAD database, including 48,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (3378 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45002 hom.)
• Consequence: TGFBI NM_000358.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44

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 -8 ACMG points.

• PP5: Variant 5-136056818-G-A is Pathogenic according to our data. Variant chr5-136056818-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBI	NM_000358.3	c.1678+23G>A		intron_variant		ENST00000442011.7	NP_000349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBI	ENST00000442011.7	c.1678+23G>A		intron_variant		1	NM_000358.3	ENSP00000416330	P1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28633 AN: 151760 Hom.: 3380 Cov.: 31

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.201

GnomAD3 exomes AF: 0.252 AC: 56330 AN: 223496 Hom.: 7600 AF XY: 0.257 AC XY: 31060 AN XY: 121046

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.341

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.245 AC: 354324 AN: 1445422 Hom.: 45002 Cov.: 32 AF XY: 0.248 AC XY: 177711 AN XY: 717626

Gnomad4 AFR exome AF: 0.0378

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.210

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.189 AC: 28642 AN: 151878 Hom.: 3378 Cov.: 31 AF XY: 0.191 AC XY: 14193 AN XY: 74198

Gnomad4 AFR AF: 0.0441

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.201

Alfa AF: 0.221 Hom.: 951

Bravo AF: 0.180

Asia WGS AF: 0.242 AC: 841 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.045
DANN	Benign	0.54

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: rs2072239; hg19: chr5-135392507; COSMIC: COSV59353895; COSMIC: COSV59353895;