16-2046208-G-C

Variant names:

• chr16-2046208-G-C
• rs148104494
• NM_002528.7:c.274C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002528.7(NTHL1):​c.274C>G​(p.Arg92Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R92C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTHL1 NM_002528.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

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.274C>G	p.Arg92Gly	missense	Exon 2 of 6	NP_002519.2
	NTHL1	NM_001318193.2		c.274C>G	p.Arg92Gly	missense	Exon 2 of 5	NP_001305122.2
	NTHL1	NM_001318194.2		c.24+72C>G		intron	N/A	NP_001305123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTHL1	ENST00000651570.2	MANE Select	c.274C>G	p.Arg92Gly	missense	Exon 2 of 6	ENSP00000498421.1
	NTHL1	ENST00000219066.5	TSL:1	c.298C>G	p.Arg100Gly	missense	Exon 2 of 6	ENSP00000219066.1
	NTHL1	ENST00000566380.5	TSL:3	c.235C>G	p.Arg79Gly	missense	Exon 2 of 5	ENSP00000455267.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		5.7
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.22	B
Vest4		0.89
MutPred		0.58		Loss of MoRF binding (P = 0.0127)
MVP		0.48
MPC		0.18
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		0.018	Neutral
Varity_R		0.81
gMVP		0.78
Mutation Taster		=9/91	disease causing

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: rs148104494; hg19: chr16-2096209;