chr16-2047750-C-G

Variant names:

• chr16-2047750-C-G
• rs2302172
• NM_002528.7:c.74G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002528.7(NTHL1):​c.74G>C​(p.Arg25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NTHL1 NM_002528.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• Publications: 0 publications found

Genes affected

NTHL1 (HGNC:8028): (nth like DNA glycosylase 1) The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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 (MetaRNN=0.069782525).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002528.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTHL1	NM_002528.7	MANE Select	c.74G>C	p.Arg25Thr	missense	Exon 1 of 6	NP_002519.2
	NTHL1	NM_001318193.2		c.74G>C	p.Arg25Thr	missense	Exon 1 of 5	NP_001305122.2
	NTHL1	NM_001318194.2		c.-105G>C		5_prime_UTR	Exon 1 of 6	NP_001305123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTHL1	ENST00000651570.2	MANE Select	c.74G>C	p.Arg25Thr	missense	Exon 1 of 6	ENSP00000498421.1
	NTHL1	ENST00000219066.5	TSL:1	c.98G>C	p.Arg33Thr	missense	Exon 1 of 6	ENSP00000219066.1
	NTHL1	ENST00000566380.5	TSL:3	c.35G>C	p.Arg12Thr	missense	Exon 1 of 5	ENSP00000455267.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434404 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712646

African (AFR) AF: 0.00 AC: 0 AN: 32938

American (AMR) AF: 0.00 AC: 0 AN: 43382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 38548

South Asian (SAS) AF: 0.00 AC: 0 AN: 83530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104384

Other (OTH) AF: 0.00 AC: 0 AN: 59556

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.64
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.28
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.023
Sift	Benign	0.16	T
Sift4G	Benign	0.54	T
Polyphen		0.0040	B
Vest4		0.21
MutPred		0.22		Gain of phosphorylation at R33 (P = 0.0028)
MVP		0.055
MPC		0.090
ClinPred		0.093	T
GERP RS		1.2
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.35
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs2302172; hg19: chr16-2097751;