rs1800471

Positions:

• chr19-41352971-C-G
• chr19-41352971-C-T

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.74G>C​(p.Arg25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0711 in 1,543,868 control chromosomes in the GnomAD database, including 4,202 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 UniProt.

• Frequency:
  • Genomes: 𝑓 0.063 (356 hom., cov: 32)
  • Exomes 𝑓: 0.072 (3846 hom.)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.754

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=0.002168864).
• BP6: Variant 19-41352971-C-G is Benign according to our data. Variant chr19-41352971-C-G is described in ClinVar as [Benign]. Clinvar id is 38902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41352971-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.74G>C	p.Arg25Pro	missense_variant	1/7	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.74G>C	p.Arg25Pro	missense_variant	1/7		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.74G>C	p.Arg25Pro	missense_variant	1/7	1	NM_000660.7	ENSP00000221930	P1
TMEM91	ENST00000539627.5	c.-30+1769C>G		intron_variant		1		ENSP00000441900
TGFB1	ENST00000600196.2	c.74G>C	p.Arg25Pro	missense_variant	1/6	5		ENSP00000504008
TGFB1	ENST00000677934.1	c.74G>C	p.Arg25Pro	missense_variant	1/5			ENSP00000504769

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9580 AN: 152132 Hom.: 354 Cov.: 32

Gnomad AFR AF: 0.0647

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0750

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.0550

GnomAD3 exomes AF: 0.0565 AC: 8035 AN: 142282 Hom.: 245 AF XY: 0.0592 AC XY: 4571 AN XY: 77192

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.000818

Gnomad SAS exome AF: 0.0783

Gnomad FIN exome AF: 0.0347

Gnomad NFE exome AF: 0.0732

Gnomad OTH exome AF: 0.0571

GnomAD4 exome AF: 0.0719 AC: 100121 AN: 1391618 Hom.: 3846 Cov.: 33 AF XY: 0.0717 AC XY: 49252 AN XY: 687184

Gnomad4 AFR exome AF: 0.0623

Gnomad4 AMR exome AF: 0.0369

Gnomad4 ASJ exome AF: 0.0412

Gnomad4 EAS exome AF: 0.000390

Gnomad4 SAS exome AF: 0.0759

Gnomad4 FIN exome AF: 0.0394

Gnomad4 NFE exome AF: 0.0777

Gnomad4 OTH exome AF: 0.0662

GnomAD4 genome AF: 0.0630 AC: 9586 AN: 152250 Hom.: 356 Cov.: 32 AF XY: 0.0607 AC XY: 4518 AN XY: 74438

Gnomad4 AFR AF: 0.0645

Gnomad4 AMR AF: 0.0407

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.0761

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.0544

Alfa AF: 0.0554 Hom.: 95

Bravo AF: 0.0629

TwinsUK AF: 0.0798 AC: 296

ALSPAC AF: 0.0838 AC: 323

ESP6500AA AF: 0.0454 AC: 187

ESP6500EA AF: 0.0491 AC: 396

ExAC AF: 0.0264 AC: 2615

Asia WGS AF: 0.0300 AC: 104 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.97
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.067
Sift	Benign	0.25	T
Sift4G	Benign	0.28	T
Vest4		0.16
MPC		2.0
ClinPred		0.018	T
GERP RS		2.8

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: rs1800471; hg19: chr19-41858876;