19-7916742-G-C

Position:

• chr19-7916742-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001195259.2(TGFBR3L):​c.397G>C​(p.Asp133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,338,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: TGFBR3L NM_001195259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR3L	NM_001195259.2	c.397G>C	p.Asp133His	missense_variant	2/6	ENST00000565886.2	NP_001182188.1
TGFBR3L	XM_011527610.3	c.475G>C	p.Asp159His	missense_variant	1/4		XP_011525912.1
TGFBR3L	XM_011527613.3	c.475G>C	p.Asp159His	missense_variant	1/5		XP_011525915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR3L	ENST00000565886.2	c.397G>C	p.Asp133His	missense_variant	2/6	5	NM_001195259.2	ENSP00000457962	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000299 AC: 4 AN: 1338848 Hom.: 0 Cov.: 31 AF XY: 0.00000454 AC XY: 3 AN XY: 660216

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: 0.00000378

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jan 18, 2022

The c.397G>C (p.D133H) alteration is located in exon 2 (coding exon 2) of the TGFBR3L gene. This alteration results from a G to C substitution at nucleotide position 397, causing the aspartic acid (D) at amino acid position 133 to be replaced by a histidine (H). 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	0.83
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	D
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.10	T
Vest4		0.53
MVP		0.85
GERP RS		3.3
Varity_R		0.54
gMVP		0.63

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: rs1003150613; hg19: chr19-7981627;