chr19-7917739-G-C

Position:

• chr19-7917739-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195259.2(TGFBR3L):​c.763G>C​(p.Glu255Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000782 in 1,278,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: TGFBR3L NM_001195259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.270

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]

TGFBR3L (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07556802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR3L	NM_001195259.2	c.763G>C	p.Glu255Gln	missense_variant	4/6	ENST00000565886.2	NP_001182188.1
TGFBR3L	NM_001419781.1	c.691G>C	p.Glu231Gln	missense_variant	5/7		NP_001406710.1
TGFBR3L	XM_011527613.3	c.841G>C	p.Glu281Gln	missense_variant	3/5		XP_011525915.1
TGFBR3L	XM_011527610.3	c.942G>C	p.Leu314Leu	synonymous_variant	2/4		XP_011525912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR3L	ENST00000565886.2	c.763G>C	p.Glu255Gln	missense_variant	4/6	5	NM_001195259.2
TGFBR3L	ENST00000564348.5	n.261G>C		non_coding_transcript_exon_variant	3/5	5
TGFBR3L	ENST00000566166.1	n.112G>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.82e-7 AC: 1 AN: 1278616 Hom.: 0 Cov.: 32 AF XY: 0.00000160 AC XY: 1 AN XY: 625598

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: 0.0000153

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000754 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2024

The c.763G>C (p.E255Q) alteration is located in exon 4 (coding exon 4) of the TGFBR3L gene. This alteration results from a G to C substitution at nucleotide position 763, causing the glutamic acid (E) at amino acid position 255 to be replaced by a glutamine (Q). 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	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.3
DANN	Benign	0.72
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.076	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.94	N
Sift	Benign	0.44	T
Sift4G	Benign	0.23	T
Vest4		0.057
MVP		0.59
GERP RS		-0.82
Varity_R		0.098
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs757194543; hg19: chr19-7982624;