15-75349131-G-A

Position:

• chr15-75349131-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024608.4(NEIL1):​c.226G>A​(p.Val76Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEIL1 NM_024608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

NEIL1 (HGNC:18448): (nei like DNA glycosylase 1) This gene is a member of the Nei endonuclease VIII-like gene family which encodes DNA glycosylases. The encoded enzyme participates in the DNA repair pathway by initiating base excision repair by removing damaged bases, primarily oxidized pyrimidines. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

NEIL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16730368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEIL1	NM_024608.4	c.226G>A	p.Val76Ile	missense_variant	2/10	ENST00000355059.9	NP_078884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEIL1	ENST00000355059.9	c.226G>A	p.Val76Ile	missense_variant	2/10	2	NM_024608.4	ENSP00000347170.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2024

The c.226G>A (p.V76I) alteration is located in exon 2 (coding exon 1) of the NEIL1 gene. This alteration results from a G to A substitution at nucleotide position 226, causing the valine (V) at amino acid position 76 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.042	T;.;T;T;T;.;.;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	.;T;T;.;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;.;L;L;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.19	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.082	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T
Polyphen		0.0040	B;.;.;B;B;.;.;.;.
Vest4		0.082
MutPred		0.65		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.22
MPC		0.17
ClinPred		0.27	T
GERP RS		1.4
Varity_R		0.049
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2071676358; hg19: chr15-75641472;