rs950957418

Variant names:

• chr16-2039929-G-A
• rs950957418
• NM_002528.7:c.910C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2039929-G-A
• chr16-2039929-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002528.7(NTHL1):​c.910C>T​(p.Leu304Phe) variant causes a missense 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. 16/22 in silico tools predict a benign 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. L304H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTHL1 NM_002528.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.995
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06121376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTHL1	NM_002528.7	c.910C>T	p.Leu304Phe	missense_variant	Exon 6 of 6	ENST00000651570.2	NP_002519.2
NTHL1	NM_001318193.2	c.739C>T	p.Leu247Phe	missense_variant	Exon 5 of 5		NP_001305122.2
NTHL1	NM_001318194.2	c.580C>T	p.Leu194Phe	missense_variant	Exon 6 of 6		NP_001305123.1
NTHL1	XM_047434171.1	c.631C>T	p.Leu211Phe	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.910C>T	p.Leu304Phe	missense_variant	Exon 6 of 6		NM_002528.7	ENSP00000498421.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.99
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.026
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.078
MutPred		0.40		Gain of catalytic residue at L312 (P = 0.1193);
MVP		0.055
MPC		0.067
ClinPred		0.15	T
GERP RS		0.85
Varity_R		0.038
gMVP		0.66
Mutation Taster		=98/2	polymorphism

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: rs950957418; hg19: chr16-2089930;