rs147601018

Variant names:

• chr14-75963429-C-G
• rs147601018
• NM_003239.5:c.813G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-75963429-C-G
• chr14-75963429-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_003239.5(TGFB3):​c.813G>C​(p.Lys271Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,611,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K271R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TGFB3 NM_003239.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.27
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13509125).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000867 (13/149936) while in subpopulation NFE AF = 0.000193 (13/67274). AF 95% confidence interval is 0.000113. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.813G>C	p.Lys271Asn	missense	Exon 5 of 7	NP_003230.1	A5YM40
	TGFB3	NM_001329939.2		c.813G>C	p.Lys271Asn	missense	Exon 6 of 8	NP_001316868.1	A5YM40
	TGFB3	NM_001329938.2		c.813G>C	p.Lys271Asn	missense	Exon 5 of 5	NP_001316867.1	P10600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB3	ENST00000238682.8	TSL:1 MANE Select	c.813G>C	p.Lys271Asn	missense	Exon 5 of 7	ENSP00000238682.3	P10600-1
	TGFB3	ENST00000556285.1	TSL:1	c.813G>C	p.Lys271Asn	missense	Exon 5 of 5	ENSP00000451110.1	P10600-2
	TGFB3	ENST00000964917.1		c.975G>C	p.Lys325Asn	missense	Exon 6 of 8	ENSP00000634976.1

Frequencies

GnomAD3 genomes AF: 0.0000867 AC: 13 AN: 149936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000193

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 20 AN: 251456 AF XY: 0.0000515

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: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 168 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93 AN XY: 727246

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: 53418

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

European-Non Finnish (NFE) AF: 0.000150 AC: 167 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000867 AC: 13 AN: 149936 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 8 AN XY: 73236

African (AFR) AF: 0.00 AC: 0 AN: 40598

American (AMR) AF: 0.00 AC: 0 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000193 AC: 13 AN: 67274

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not specified (1)
-	1	-	Rienhoff syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.028
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.10
Sift	Benign	0.42	T
Sift4G	Benign	0.42	T
Polyphen		0.017	B
Vest4		0.61
MutPred		0.32		Gain of ubiquitination at K269 (P = 0.0222)
MVP		0.56
MPC		1.6
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.86
Mutation Taster		=62/38	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: rs147601018; hg19: chr14-76429772;