16-2039934-TGGGCGGCC-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_002528.7(NTHL1):c.897_904del(p.Ala300GlyfsTer19) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P299P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTHL1 NM_002528.7 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.66

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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0197 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTHL1	NM_002528.7	c.897_904del	p.Ala300GlyfsTer19	frameshift_variant	6/6	ENST00000651570.2
NTHL1	NM_001318193.2	c.726_733del	p.Ala243GlyfsTer19	frameshift_variant	5/5
NTHL1	NM_001318194.2	c.567_574del	p.Ala190GlyfsTer19	frameshift_variant	6/6
NTHL1	XM_047434171.1	c.618_625del	p.Ala207GlyfsTer19	frameshift_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTHL1	ENST00000651570.2	c.897_904del	p.Ala300GlyfsTer19	frameshift_variant	6/6		NM_002528.7

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 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. ClinVar contains an entry for this variant (Variation ID: 657015). 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 results in a frameshift in the NTHL1 gene (p.Ala308Glyfs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the NTHL1 protein and extend the protein by 13 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1596215933; hg19: chr16-2089935;