14-75980543-G-C

Variant names:

• chr14-75980543-G-C
• rs375232060
• NM_003239.5:c.351C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003239.5(TGFB3):​c.351C>G​(p.His117Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H117H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TGFB3 NM_003239.5 missense, splice_region
• Scores: Splicing: ADA: 0.008386
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23
• 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: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31720233).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	NM_003239.5	MANE Select	c.351C>G	p.His117Gln	missense splice_region	Exon 1 of 7	NP_003230.1
	TGFB3	NM_001329939.2		c.351C>G	p.His117Gln	missense splice_region	Exon 2 of 8	NP_001316868.1
	TGFB3	NM_001329938.2		c.351C>G	p.His117Gln	missense splice_region	Exon 1 of 5	NP_001316867.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.351C>G	p.His117Gln	missense splice_region	Exon 1 of 7	ENSP00000238682.3
	TGFB3	ENST00000556285.1	TSL:1	c.351C>G	p.His117Gln	missense splice_region	Exon 1 of 5	ENSP00000451110.1
	TGFB3	ENST00000556674.2	TSL:3	c.351C>G	p.His117Gln	missense splice_region	Exon 2 of 8	ENSP00000502685.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0063	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.19
Sift	Benign	0.16	T
Sift4G	Benign	0.51	T
Polyphen		0.022	B
Vest4		0.26
MutPred		0.44		Gain of catalytic residue at H117 (P = 0.0041)
MVP		0.55
MPC		0.61
ClinPred		0.85	D
GERP RS		4.8
PromoterAI		-0.0038	Neutral
Varity_R		0.14
gMVP		0.54
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0084
dbscSNV1_RF	Benign	0.074
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: rs375232060; hg19: chr14-76446886;