chr15-75349179-G-C

Variant names:

• chr15-75349179-G-C
• rs764632635
• NM_024608.4:c.274G>C

Variant summary

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

The NM_024608.4(NEIL1):​c.274G>C​(p.Glu92Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,608,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E92V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEIL1 NM_024608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96
• Publications: 2 publications found

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]

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=0.046049625).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024608.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	NM_024608.4	MANE Select	c.274G>C	p.Glu92Gln	missense	Exon 2 of 10	NP_078884.2	Q96FI4
	NEIL1	NM_001256552.1		c.532G>C	p.Glu178Gln	missense	Exon 2 of 10	NP_001243481.1	Q96FI4
	NEIL1	NM_001352519.2		c.-62G>C		5_prime_UTR	Exon 2 of 6	NP_001339448.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL1	ENST00000355059.9	TSL:2 MANE Select	c.274G>C	p.Glu92Gln	missense	Exon 2 of 10	ENSP00000347170.4	Q96FI4
	NEIL1	ENST00000569035.5	TSL:1	c.274G>C	p.Glu92Gln	missense	Exon 2 of 10	ENSP00000455730.1	Q96FI4
	NEIL1	ENST00000866915.1		c.274G>C	p.Glu92Gln	missense	Exon 2 of 9	ENSP00000536974.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000408 AC: 10 AN: 245376 AF XY: 0.0000524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000494

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456684 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 724922

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111854

Other (OTH) AF: 0.00 AC: 0 AN: 60318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000852049), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.028
Sift	Benign	0.49	T
Sift4G	Benign	0.34	T
Polyphen		0.077	B
Vest4		0.10
MutPred		0.41		Loss of disorder (P = 0.1621)
MVP		0.30
MPC		0.17
ClinPred		0.026	T
GERP RS		1.1
Varity_R		0.26
gMVP		0.39
Mutation Taster		=90/10	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: rs764632635; hg19: chr15-75641520;