chr19-41353016-G-A

Variant names:

• chr19-41353016-G-A
• rs1800470
• NM_000660.7:c.29C>T

Variant summary

Our verdict is Benign. The variant received -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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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:9 O:2
• Conservation: PhyloP100: 0.760
• Publications: 1023 publications found

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]

ENSG00000255730 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 12534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000660.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB1	NM_000660.7	MANE Select	c.29C>T	p.Pro10Leu	missense	Exon 1 of 7	NP_000651.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB1	ENST00000221930.6	TSL:1 MANE Select	c.29C>T	p.Pro10Leu	missense	Exon 1 of 7	ENSP00000221930.4
	TMEM91	ENST00000539627.5	TSL:1	c.-30+1814G>A		intron	N/A	ENSP00000441900.1
	TGFB1	ENST00000890114.1		c.29C>T	p.Pro10Leu	missense	Exon 1 of 7	ENSP00000560173.1

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

GnomAD2 exomes AF: 0.552 AC: 71740 AN: 129938 AF XY: 0.554

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 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

African (AFR) AF: 0.565 AC: 17554 AN: 31090

American (AMR) AF: 0.482 AC: 16982 AN: 35234

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12273 AN: 24976

East Asian (EAS) AF: 0.479 AC: 16943 AN: 35366

South Asian (SAS) AF: 0.538 AC: 42395 AN: 78740

European-Finnish (FIN) AF: 0.712 AC: 25060 AN: 35208

Middle Eastern (MID) AF: 0.518 AC: 2921 AN: 5640

European-Non Finnish (NFE) AF: 0.622 AC: 666557 AN: 1072344

Other (OTH) AF: 0.581 AC: 33377 AN: 57406

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

African (AFR) AF: 0.574 AC: 23818 AN: 41480

American (AMR) AF: 0.517 AC: 7911 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1736 AN: 3468

East Asian (EAS) AF: 0.444 AC: 2270 AN: 5110

South Asian (SAS) AF: 0.544 AC: 2622 AN: 4824

European-Finnish (FIN) AF: 0.714 AC: 7562 AN: 10598

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41468 AN: 67896

Other (OTH) AF: 0.559 AC: 1182 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Diaphyseal dysplasia (1)
-	-	1	Inflammatory bowel disease, immunodeficiency, and encephalopathy (1)
-	-	1	Meckel syndrome, type 10 (1)
-	-	-	Breast cancer, invasive, susceptibility to (1)
-	-	-	Cystic fibrosis (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.76
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
PromoterAI		-0.0049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=49/51	disease causing

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

Other links and lift over

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