rs1800470

chr19-41353016-G-Achr19-41353016-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000660.7(TGFB1):c.29C>T(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,527,994 control chromosomes in the GnomAD database, including 280,580 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (26724 hom., cov: 33)
  • Exomes 𝑓: 0.61 (253856 hom.)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:2
• Conservation: PhyloP100: 0.760

Genes affected

TGFB1 (HGNC:11766): (transforming growth factor beta 1) 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 TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7511124E-6).
• BP6: Variant 19-41353016-G-A is Benign according to our data. Variant chr19-41353016-G-A is described in ClinVar as [Benign]. Clinvar id is 12534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41353016-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB1	NM_000660.7	c.29C>T	p.Pro10Leu	missense_variant	1/7	ENST00000221930.6
TGFB1	XM_011527242.3	c.29C>T	p.Pro10Leu	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB1	ENST00000221930.6	c.29C>T	p.Pro10Leu	missense_variant	1/7	1	NM_000660.7	P1
TMEM91	ENST00000539627.5	c.-30+1814G>A		intron_variant		1
TGFB1	ENST00000600196.2	c.29C>T	p.Pro10Leu	missense_variant	1/6	5
TGFB1	ENST00000677934.1	c.29C>T	p.Pro10Leu	missense_variant	1/5

Frequencies

GnomAD3 genomes AF: 0.589 AC: 89408 AN: 151872 Hom.: 26723 Cov.: 33

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.563

GnomAD3 exomes AF: 0.552 AC: 71740 AN: 129938 Hom.: 19769 AF XY: 0.554 AC XY: 39248 AN XY: 70790

Gnomad AFR exome AF: 0.567

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.707

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.606 AC: 834062 AN: 1376004 Hom.: 253856 Cov.: 55 AF XY: 0.603 AC XY: 409363 AN XY: 678490

Gnomad4 AFR exome AF: 0.565

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.479

Gnomad4 SAS exome AF: 0.538

Gnomad4 FIN exome AF: 0.712

Gnomad4 NFE exome AF: 0.622

Gnomad4 OTH exome AF: 0.581

GnomAD4 genome AF: 0.588 AC: 89439 AN: 151990 Hom.: 26724 Cov.: 33 AF XY: 0.589 AC XY: 43749 AN XY: 74304

Gnomad4 AFR AF: 0.574

Gnomad4 AMR AF: 0.517

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.714

Gnomad4 NFE AF: 0.611

Gnomad4 OTH AF: 0.559

Alfa AF: 0.504 Hom.: 2560

Bravo AF: 0.573

TwinsUK AF: 0.629 AC: 2334

ALSPAC AF: 0.622 AC: 2398

ExAC AF: 0.488 AC: 27708

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inflammatory bowel disease, immunodeficiency, and encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Meckel syndrome, type 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Diaphyseal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Cystic fibrosis Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 15, 2008

- -

Breast cancer, invasive, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000058	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	4.1e-11	P;P
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.017
Sift	Benign	0.83	T
Sift4G	Benign	0.18	T
Vest4		0.098
MPC		0.67
ClinPred		0.0082	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1800470; hg19: chr19-41858921; COSMIC: COSV54683540; COSMIC: COSV54683540;