19-41352691-G-C

Variant names:

• chr19-41352691-G-C
• rs2038222572
• NM_000660.7:c.354C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000660.7(TGFB1):​c.354C>G​(p.Asn118Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N118N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFB1 NM_000660.7 missense, splice_region
• Scores: Splicing: ADA: 0.0004846
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.265
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a chain Latency-associated peptide (size 248) in uniprot entity TGFB1_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_000660.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14418447).

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.354C>G	p.Asn118Lys	missense splice_region	Exon 1 of 7	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.354C>G	p.Asn118Lys	missense splice_region	Exon 1 of 7	ENSP00000221930.4	A0A499FJK2
	TMEM91	ENST00000539627.5	TSL:1	c.-30+1489G>C		intron	N/A	ENSP00000441900.1	F5GWC9
	TGFB1	ENST00000890114.1		c.354C>G	p.Asn118Lys	missense splice_region	Exon 1 of 7	ENSP00000560173.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461010 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726818

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111868

Other (OTH) AF: 0.0000166 AC: 1 AN: 60362

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.78
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.27
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.082
Sift	Benign	0.082	T
Sift4G	Benign	0.44	T
Vest4		0.090
MutPred		0.58		Gain of ubiquitination at N118 (P = 0.0185)
MVP		0.66
MPC		0.76
ClinPred		0.24	T
GERP RS		0.12
PromoterAI		-0.056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2038222572; hg19: chr19-41858596;