chr16-2039931-C-A

Variant names:

• chr16-2039931-C-A
• rs2084235801
• NM_002528.7:c.908G>T

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.908G>T​(p.Gly303Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G303R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NTHL1 NM_002528.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.813
• 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]

NTHL1 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• NTHL1-deficiency tumor predisposition syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• breast cancer

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• meningioma

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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=0.09479824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTHL1	NM_002528.7	c.908G>T	p.Gly303Val	missense_variant	Exon 6 of 6	ENST00000651570.2	NP_002519.2
NTHL1	NM_001318193.2	c.737G>T	p.Gly246Val	missense_variant	Exon 5 of 5		NP_001305122.2
NTHL1	NM_001318194.2	c.578G>T	p.Gly193Val	missense_variant	Exon 6 of 6		NP_001305123.1
NTHL1	XM_047434171.1	c.629G>T	p.Gly210Val	missense_variant	Exon 6 of 6		XP_047290127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTHL1	ENST00000651570.2	c.908G>T	p.Gly303Val	missense_variant	Exon 6 of 6		NM_002528.7	ENSP00000498421.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450092 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721672

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 845921). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 311 of the NTHL1 protein (p.Gly311Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.39	N
PhyloP100		0.81
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.060
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.17	T
Polyphen		0.31	B
Vest4		0.13
MutPred		0.36		Gain of stability (P = 0.0212);
MVP		0.092
MPC		0.12
ClinPred		0.12	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.68
Mutation Taster		=99/1	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: rs2084235801; hg19: chr16-2089932;