rs121909217

Variant names:

• chr5-136062674-G-A
• rs121909217
• NM_000358.3:c.1998G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-136062674-G-A
• chr5-136062674-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000358.3(TGFBI):​c.1998G>A​(p.Arg666Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFBI NM_000358.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.483
• Publications: 14 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=-0.483 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBI	NM_000358.3	MANE Select	c.1998G>A	p.Arg666Arg	synonymous	Exon 16 of 17	NP_000349.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBI	ENST00000442011.7	TSL:1 MANE Select	c.1998G>A	p.Arg666Arg	synonymous	Exon 16 of 17	ENSP00000416330.2
	TGFBI	ENST00000508076.5	TSL:2	c.144G>A	p.Arg48Arg	synonymous	Exon 5 of 6	ENSP00000423935.1
	TGFBI	ENST00000504411.1	TSL:2	n.402G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 182164 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1415562 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699558

African (AFR) AF: 0.00 AC: 0 AN: 32560

American (AMR) AF: 0.00 AC: 0 AN: 38134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25406

East Asian (EAS) AF: 0.00 AC: 0 AN: 37688

South Asian (SAS) AF: 0.00 AC: 0 AN: 80324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086566

Other (OTH) AF: 0.00 AC: 0 AN: 58692

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.6
DANN	Benign	0.80
PhyloP100		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121909217; hg19: chr5-135398363;