rs2241715

Positions:

• chr19-41350981-A-C
• chr19-41350981-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000539627.5(TMEM91):​c.-251A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 152,260 control chromosomes in the GnomAD database, including 34,737 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (34659 hom., cov: 30)
  • Exomes 𝑓: 0.61 (78 hom.)
• Consequence: TMEM91 ENST00000539627.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.51

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.355+1709T>G		intron_variant		ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.355+1709T>G		intron_variant			XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM91	ENST00000539627.5	c.-251A>C		5_prime_UTR_variant	1/3	1		ENSP00000441900
TGFB1	ENST00000221930.6	c.355+1709T>G		intron_variant		1	NM_000660.7	ENSP00000221930	P1
TGFB1	ENST00000600196.2	c.355+1709T>G		intron_variant		5		ENSP00000504008
TGFB1	ENST00000677934.1	c.355+1709T>G		intron_variant				ENSP00000504769

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101794 AN: 151702 Hom.: 34643 Cov.: 30

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.743

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.630

GnomAD4 exome AF: 0.611 AC: 270 AN: 442 Hom.: 78 Cov.: 0 AF XY: 0.615 AC XY: 161 AN XY: 262

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.462

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.635

Gnomad4 NFE exome AF: 0.645

Gnomad4 OTH exome AF: 0.538

GnomAD4 genome AF: 0.671 AC: 101855 AN: 151818 Hom.: 34659 Cov.: 30 AF XY: 0.668 AC XY: 49528 AN XY: 74176

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.611

Gnomad4 FIN AF: 0.743

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.626

Alfa AF: 0.667 Hom.: 41407

Bravo AF: 0.658

Asia WGS AF: 0.537 AC: 1864 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.91
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.95

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: rs2241715; hg19: chr19-41856886;