rs11466318

Variant names:

• chr19-41352685-C-T
• rs11466318
• NM_000660.7:c.355+5G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_000660.7(TGFB1):​c.355+5G>A variant causes a splice region, 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_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.43
• Publications: 2 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 19-41352685-C-T is Benign according to our data. Variant chr19-41352685-C-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB1	NM_000660.7	MANE Select	c.355+5G>A		splice_region intron	N/A	NP_000651.3	P01137

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB1	ENST00000221930.6	TSL:1 MANE Select	c.355+5G>A		splice_region intron	N/A	ENSP00000221930.4	A0A499FJK2
	TMEM91	ENST00000539627.5	TSL:1	c.-30+1483C>T		intron	N/A	ENSP00000441900.1	F5GWC9
	TGFB1	ENST00000890114.1		c.355+5G>A		splice_region intron	N/A	ENSP00000560173.1

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1222 AN: 152112 Hom.: 21 Cov.: 31

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

GnomAD2 exomes AF: 0.00218 AC: 532 AN: 243910 AF XY: 0.00160

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 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.: 26 Cov.: 32 AF XY: 0.000820 AC XY: 596 AN XY: 726702

African (AFR) AF: 0.0331 AC: 1109 AN: 33466

American (AMR) AF: 0.00137 AC: 61 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52668

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5754

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111842

Other (OTH) AF: 0.00186 AC: 112 AN: 60372

GnomAD4 genome AF: 0.00806 AC: 1227 AN: 152232 Hom.: 22 Cov.: 31 AF XY: 0.00751 AC XY: 559 AN XY: 74416

African (AFR) AF: 0.0280 AC: 1165 AN: 41538

American (AMR) AF: 0.00333 AC: 51 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00401 Hom.: 4

Bravo AF: 0.00925

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cystic fibrosis;C0011989:Diaphyseal dysplasia;C4748708:Inflammatory bowel disease, immunodeficiency, and encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.89
PhyloP100		3.4
PromoterAI		-0.22	Neutral
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs11466318; hg19: chr19-41858590;