chr9-132905699-G-C

Position:

• chr9-132905699-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_000368.5(TSC1):​c.1879C>G​(p.Leu627Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.68

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27053112).
• BP6: Variant 9-132905699-G-C is Benign according to our data. Variant chr9-132905699-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1781838.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1879C>G	p.Leu627Val	missense_variant	15/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1879C>G	p.Leu627Val	missense_variant	15/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1879C>G	p.Leu627Val	missense_variant	16/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251364 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2022

The p.L627V variant (also known as c.1879C>G), located in coding exon 13 of the TSC1 gene, results from a C to G substitution at nucleotide position 1879. The leucine at codon 627 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T;.;T;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.8	L;.;L;.;.;L;.;L;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.20	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.45	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.26	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.72	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.21
MutPred		0.43		Gain of methylation at K630 (P = 0.0575);.;Gain of methylation at K630 (P = 0.0575);.;.;Gain of methylation at K630 (P = 0.0575);.;Gain of methylation at K630 (P = 0.0575);.;Gain of methylation at K630 (P = 0.0575);.;
MVP		0.66
MPC		0.82
ClinPred		0.33	T
GERP RS		5.9
Varity_R		0.071
gMVP		0.27

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: rs1171110012; hg19: chr9-135781086;