NM_000368.5:c.917G>A

Variant names:

• chr9-132911565-C-T
• rs752290177
• NM_000368.5:c.917G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000368.5(TSC1):​c.917G>A​(p.Cys306Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000679 in 1,472,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C306R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: -0.112
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 29 uncertain in NM_000368.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.11152014).
• BP6: Variant 9-132911565-C-T is Benign according to our data. Variant chr9-132911565-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 466161.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. 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
	TSC1	NM_000368.5	MANE Select	c.917G>A	p.Cys306Tyr	missense	Exon 10 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406626.1		c.-35G>A		5_prime_UTR_premature_start_codon_gain	Exon 9 of 22	NP_001393555.1
	TSC1	NM_001406627.1		c.-35G>A		5_prime_UTR_premature_start_codon_gain	Exon 9 of 22	NP_001393556.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.917G>A	p.Cys306Tyr	missense	Exon 10 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.917G>A	p.Cys306Tyr	missense	Exon 11 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000403810.6	TSL:1	c.917G>A	p.Cys306Tyr	missense	Exon 10 of 10	ENSP00000386093.1	Q86WV8

Frequencies

GnomAD3 genomes AF: 0.0000225 AC: 3 AN: 133284 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000546

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250906 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000523 AC: 7 AN: 1339598 Hom.: 0 Cov.: 30 AF XY: 0.00000751 AC XY: 5 AN XY: 665774

African (AFR) AF: 0.000164 AC: 5 AN: 30404

American (AMR) AF: 0.0000243 AC: 1 AN: 41218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22096

East Asian (EAS) AF: 0.00 AC: 0 AN: 29458

South Asian (SAS) AF: 0.00 AC: 0 AN: 84940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4718

European-Non Finnish (NFE) AF: 9.72e-7 AC: 1 AN: 1028848

Other (OTH) AF: 0.00 AC: 0 AN: 52846

GnomAD4 genome AF: 0.0000225 AC: 3 AN: 133284 Hom.: 0 Cov.: 28 AF XY: 0.0000159 AC XY: 1 AN XY: 62874

African (AFR) AF: 0.0000556 AC: 2 AN: 35958

American (AMR) AF: 0.00 AC: 0 AN: 11534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 4028

South Asian (SAS) AF: 0.00 AC: 0 AN: 3958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64870

Other (OTH) AF: 0.000546 AC: 1 AN: 1830

Alfa AF: 0.0000533 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	1	Tuberous sclerosis 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.68
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.46
Sift	Benign	0.18	T
Sift4G	Uncertain	0.041	D
Polyphen		0.032	B
Vest4		0.20
MutPred		0.38		Gain of phosphorylation at C306 (P = 0.0403)
MVP		0.49
MPC		1.2
ClinPred		0.19	T
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.35
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752290177; hg19: chr9-135786952;