19-7916646-C-T

Variant names:

• chr19-7916646-C-T
• NM_001195259.2:c.301C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001195259.2(TGFBR3L):​c.301C>T​(p.Arg101Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000787 in 1,270,078 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: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TGFBR3L NM_001195259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.423

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41691434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR3L	NM_001195259.2	c.301C>T	p.Arg101Cys	missense_variant	Exon 2 of 6	ENST00000565886.2	NP_001182188.1
TGFBR3L	NM_001419781.1	c.229C>T	p.Arg77Cys	missense_variant	Exon 3 of 7		NP_001406710.1
TGFBR3L	XM_011527610.3	c.379C>T	p.Arg127Cys	missense_variant	Exon 1 of 4		XP_011525912.1
TGFBR3L	XM_011527613.3	c.379C>T	p.Arg127Cys	missense_variant	Exon 1 of 5		XP_011525915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR3L	ENST00000565886.2	c.301C>T	p.Arg101Cys	missense_variant	Exon 2 of 6	5	NM_001195259.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.87e-7 AC: 1 AN: 1270078 Hom.: 0 Cov.: 31 AF XY: 0.00000161 AC XY: 1 AN XY: 619224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000190

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.301C>T (p.R101C) alteration is located in exon 2 (coding exon 2) of the TGFBR3L gene. This alteration results from a C to T substitution at nucleotide position 301, causing the arginine (R) at amino acid position 101 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.42	T
MutationAssessor	Benign	1.2	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.2	D
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.034	D
Vest4		0.21
MVP		0.88
GERP RS		0.14
Varity_R		0.13
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-7981531;