chr14-75958704-TA-T

Variant names:

• chr14-75958704-TA-T
• rs199646113
• NM_003239.5:c.*482delT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_003239.5(TGFB3):​c.*482delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.071 in 173,256 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (7 hom., cov: 31)
  • Exomes 𝑓: 0.32 (0 hom.)
• Consequence: TGFB3 NM_003239.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.68
• Publications: 0 publications found

Genes affected

TGFB3 (HGNC:11769): (transforming growth factor beta 3) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. This protein is involved in embryogenesis and cell differentiation, and may play a role in wound healing. Mutations in this gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1. [provided by RefSeq, Aug 2016]

IFT43 (HGNC:29669): (intraflagellar transport 43) This gene encodes a subunit of the intraflagellar transport complex A (IFT-A). IFT-A is a multiprotein complex that plays an important role in cilia assembly and maintenance by mediating retrograde ciliary transport. Mutations in this gene are a cause of cranioectodermal dysplasia-3 (CED3), also known as Sensenbrenner syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

IFT43 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• short-rib thoracic dysplasia 18 with polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• retinitis pigmentosa 81

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 14-75958704-TA-T is Benign according to our data. Variant chr14-75958704-TA-T is described in ClinVar as Benign. ClinVar VariationId is 1269859.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003239.5. 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
	TGFB3	NM_003239.5	MANE Select	c.*482delT		3_prime_UTR	Exon 7 of 7	NP_003230.1	A5YM40
	TGFB3	NM_001329939.2		c.*482delT		3_prime_UTR	Exon 8 of 8	NP_001316868.1	A5YM40

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.*482delT		3_prime_UTR	Exon 7 of 7	ENSP00000238682.3	P10600-1
	TGFB3	ENST00000964917.1		c.*482delT		3_prime_UTR	Exon 8 of 8	ENSP00000634976.1
	TGFB3	ENST00000556674.2	TSL:3	c.*482delT		3_prime_UTR	Exon 8 of 8	ENSP00000502685.1	P10600-1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1820 AN: 140204 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00796

Gnomad ASJ AF: 0.00730

Gnomad EAS AF: 0.00509

Gnomad SAS AF: 0.00257

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.0126

GnomAD4 exome AF: 0.317 AC: 10470 AN: 33036 Hom.: 0 Cov.: 0 AF XY: 0.315 AC XY: 5322 AN XY: 16904

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.259 AC: 215 AN: 830

American (AMR) AF: 0.344 AC: 1052 AN: 3060

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 185 AN: 640

East Asian (EAS) AF: 0.317 AC: 698 AN: 2204

South Asian (SAS) AF: 0.312 AC: 1119 AN: 3588

European-Finnish (FIN) AF: 0.303 AC: 293 AN: 966

Middle Eastern (MID) AF: 0.295 AC: 39 AN: 132

European-Non Finnish (NFE) AF: 0.318 AC: 6323 AN: 19908

Other (OTH) AF: 0.320 AC: 546 AN: 1708

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0131 AC: 1837 AN: 140220 Hom.: 7 Cov.: 31 AF XY: 0.0143 AC XY: 971 AN XY: 67952

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0216 AC: 827 AN: 38208

American (AMR) AF: 0.00796 AC: 111 AN: 13944

Ashkenazi Jewish (ASJ) AF: 0.00730 AC: 24 AN: 3288

East Asian (EAS) AF: 0.00571 AC: 28 AN: 4902

South Asian (SAS) AF: 0.00258 AC: 11 AN: 4258

European-Finnish (FIN) AF: 0.0378 AC: 322 AN: 8514

Middle Eastern (MID) AF: 0.00714 AC: 2 AN: 280

European-Non Finnish (NFE) AF: 0.00762 AC: 488 AN: 64046

Other (OTH) AF: 0.0125 AC: 24 AN: 1914

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism

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: rs199646113; hg19: chr14-76425047; COSMIC: COSV53168811; COSMIC: COSV53168811;