16-2046383-G-T

Variant names:

• chr16-2046383-G-T
• rs2233518
• NM_002528.7:c.116-17C>A

Variant summary

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

The NM_002528.7(NTHL1):​c.116-17C>A variant causes a intron 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 (★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTHL1 NM_002528.7 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.802
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTHL1	NM_002528.7	c.116-17C>A		intron_variant	Intron 1 of 5	ENST00000651570.2	NP_002519.2
NTHL1	XM_047434171.1	c.-181C>A		5_prime_UTR_variant	Exon 2 of 6		XP_047290127.1
NTHL1	NM_001318193.2	c.116-17C>A		intron_variant	Intron 1 of 4		NP_001305122.2
NTHL1	NM_001318194.2	c.-63-17C>A		intron_variant	Intron 1 of 5		NP_001305123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTHL1	ENST00000651570.2	c.116-17C>A		intron_variant	Intron 1 of 5		NM_002528.7	ENSP00000498421.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the NTHL1 gene. It does not directly change the encoded amino acid sequence of the NTHL1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.63
DANN	Benign	0.70
PhyloP100		-0.80
BranchPoint Hunter		2.0
PromoterAI		0.0027	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2233518; hg19: chr16-2096384;