16-2039924-T-C

Variant summary

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

The NM_002528.7(NTHL1):c.915A>G(p.Ter305TrpextTer?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. *305*) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTHL1 NM_002528.7 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.544

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.0379841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTHL1	NM_002528.7	c.915A>G	p.Ter305TrpextTer?	stop_lost	6/6	ENST00000651570.2
NTHL1	NM_001318193.2	c.744A>G	p.Ter248TrpextTer?	stop_lost	5/5
NTHL1	NM_001318194.2	c.585A>G	p.Ter195TrpextTer?	stop_lost	6/6
NTHL1	XM_047434171.1	c.636A>G	p.Ter212TrpextTer?	stop_lost	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTHL1	ENST00000651570.2	c.915A>G	p.Ter305TrpextTer?	stop_lost	6/6		NM_002528.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 10, 2021

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. This variant has not been reported in the literature in individuals with NTHL1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change disrupts the translational stop signal of the NTHL1 mRNA. It is expected to extend the length of the NTHL1 protein by an uncertain number of additional amino acid residues. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2021

The c.939A>G variant (also known as p.*313Wext*37), located in coding exon 6 of the NTHL1 gene, results from an A to G substitution at nucleotide position 939. This alteration disrupts the stop codon of the NTHL1 gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 37 amino acids. The exact functional effect of the additional amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	8.7
Dann	Benign	0.81
Eigen	Uncertain	0.46
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.21	N
MutationTaster	Benign	1.0	N
Vest4		0.037
GERP RS		3.9

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2089925;