dbSNP rs17516265: TMEM91:c.-30+2938T>G (chr19-41354140-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000539627.5(TMEM91):c.-30+2938T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 261,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TMEM91
ENST00000539627.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.546

Publications

4 publications found

Variant links:

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]

TMEM91 links:

ENSG00000255730 (HGNC:):

ENSG00000255730 links:

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 Gene-Disease associations (from GenCC):

Camurati-Engelmann disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
inflammatory bowel disease, immunodeficiency, and encephalopathy
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
cystic fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TGFB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7 link	c.-1096A>C		upstream_gene_variant		ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3 link	c.-1096A>C		upstream_gene_variant			XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
TMEM91	ENST00000539627.5 link	c.-30+2938T>G	intron_variant	Intron 1 of 2	1		ENSP00000441900.1
ENSG00000255730	ENST00000604424.1 link	n.350+2938T>G	intron_variant	Intron 1 of 1	4
TGFB1	ENST00000221930.6 link	c.-1096A>C	upstream_gene_variant		1	NM_000660.7	ENSP00000221930.4
TMEM91	ENST00000604123.5 link	c.-34T>G	upstream_gene_variant		3		ENSP00000474871.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000115

AC:

AN:

261876

Hom.:

Cov.:

AF XY:

0.0000150

AC XY:

AN XY:

133372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

7474

American (AMR)

AF:

0.00

AC:

AN:

10228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9386

East Asian (EAS)

AF:

0.000125

AC:

AN:

23972

South Asian (SAS)

AF:

0.00

AC:

AN:

6038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1318

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

165426

Other (OTH)

AF:

0.00

AC:

AN:

16940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

0.55

PromoterAI

0.022

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over