NM_001195259.2:c.538C>T

Variant names:

• chr19-7916883-C-T
• rs1409385989
• NM_001419781.1:c.466C>T

Variant summary

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

The NM_001195259.2(TGFBR3L):​c.538C>T​(p.Arg180Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,356,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: TGFBR3L NM_001195259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

TGFBR3L (HGNC:44152): (transforming growth factor beta receptor 3 like) Predicted to enable glycosaminoglycan binding activity; transforming growth factor beta-activated receptor activity; and type II transforming growth factor beta receptor binding activity. Predicted to contribute to transforming growth factor beta binding activity. Predicted to be involved in several processes, including blood vessel morphogenesis; regulation of transforming growth factor beta receptor signaling pathway; and transforming growth factor beta receptor signaling pathway. Predicted to be integral component of membrane. Predicted to be active in cell surface and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000294288 (HGNC:):

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=0.29499033).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195259.2. 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
	TGFBR3L	NM_001419781.1	MANE Select	c.466C>T	p.Arg156Trp	missense	Exon 3 of 7	NP_001406710.1	H3BV60-1
	TGFBR3L	NM_001195259.2		c.538C>T	p.Arg180Trp	missense	Exon 2 of 6	NP_001182188.1	H3BV60-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFBR3L	ENST00000713907.1	MANE Select	c.466C>T	p.Arg156Trp	missense	Exon 3 of 7	ENSP00000519206.1	H3BV60-1
	TGFBR3L	ENST00000713908.1		c.466C>T	p.Arg156Trp	missense	Exon 3 of 6	ENSP00000519207.1	A0AAQ5BH11
	TGFBR3L	ENST00000869760.1		c.466C>T	p.Arg156Trp	missense	Exon 3 of 7	ENSP00000539819.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151814 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000232 AC: 1 AN: 43014 AF XY: 0.0000374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000240

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 AF: 0.00000166 AC: 2 AN: 1204778 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 587658

African (AFR) AF: 0.00 AC: 0 AN: 24402

American (AMR) AF: 0.0000707 AC: 1 AN: 14146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19428

East Asian (EAS) AF: 0.00 AC: 0 AN: 26646

South Asian (SAS) AF: 0.00 AC: 0 AN: 48674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3448

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 990658

Other (OTH) AF: 0.00 AC: 0 AN: 49046

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151814 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74158

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ 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: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.29	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Vest4		0.20
MVP		0.83
GERP RS		3.7
Varity_R		0.23
gMVP		0.37
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1409385989; hg19: chr19-7981768; COSMIC: COSV55603028; COSMIC: COSV55603028;