19-41352685-C-T

Position:

chr19-41352685-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000660.7(TGFB1):c.355+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,016 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 22 hom., cov: 31)

Exomes 𝑓: 0.00090 ( 26 hom. )

Consequence

TGFB1
NM_000660.7 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.43

Variant links:

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]

TGFB1 links:

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]

TMEM91 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 19-41352685-C-T is Benign according to our data. Variant chr19-41352685-C-T is described in ClinVar as [Benign]. Clinvar id is 978501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1227/152232) while in subpopulation AFR AF= 0.028 (1165/41538). AF 95% confidence interval is 0.0267. There are 22 homozygotes in gnomad4. There are 559 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB1	NM_000660.7 linkuse as main transcript	c.355+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000221930.6
TGFB1	XM_011527242.3 linkuse as main transcript	c.355+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
TGFB1	ENST00000221930.6 linkuse as main transcript	c.355+5G>A	splice_donor_5th_base_variant, intron_variant	1	NM_000660.7	P1
TMEM91	ENST00000539627.5 linkuse as main transcript	c.-30+1483C>T	intron_variant	1
TGFB1	ENST00000600196.2 linkuse as main transcript	c.355+5G>A	splice_donor_5th_base_variant, intron_variant	5
TGFB1	ENST00000677934.1 linkuse as main transcript	c.355+5G>A	splice_donor_5th_base_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00803

AC:

1222

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00218

AC:

532

AN:

243910

Hom.:

AF XY:

0.00160

AC XY:

213

AN XY:

133318

show subpopulations

Gnomad AFR exome

AF:

0.0302

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000832

Gnomad OTH exome

AF:

0.00150

GnomAD4 exome

AF:

0.000902

AC:

1318

AN:

1460784

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

596

AN XY:

726702

show subpopulations

Gnomad4 AFR exome

AF:

0.0331

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00186

GnomAD4 genome

AF:

0.00806

AC:

1227

AN:

152232

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

559

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0280

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.00925

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cystic fibrosis;C0011989:Diaphyseal dysplasia;C4748708:Inflammatory bowel disease, immunodeficiency, and encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jul 07, 2022

This variant has not been reported in the literature. This variant is present in the Genome Aggregation Database (Highest reported MAF: 2.8% [1159/41416], including 20 homozygotes; https://gnomad.broadinstitute.org/variant/19-41352685-C-T?dataset=gnomad_r3), and in ClinVar (Variation ID:978501). Splice prediction tools suggest that this variant weakens the canonical splice donor site. However, given this variant's frequency in the population and presence in the homozygous state in numerous individuals, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over