15-75349051-C-G

Position:

• chr15-75349051-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024608.4(NEIL1):​c.146C>G​(p.Ala49Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000713 in 1,613,548 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (19 hom.)
• Consequence: NEIL1 NM_024608.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.11

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044881403).
• BP6: Variant 15-75349051-C-G is Benign according to our data. Variant chr15-75349051-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 771476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000662 (968/1461168) while in subpopulation AMR AF= 0.0196 (876/44724). AF 95% confidence interval is 0.0185. There are 19 homozygotes in gnomad4_exome. There are 405 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEIL1	NM_024608.4	c.146C>G	p.Ala49Gly	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.146C>G	p.Ala49Gly	missense_variant	2/10	2	NM_024608.4	ENSP00000347170.4

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152262 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00291 AC: 730 AN: 250550 Hom.: 16 AF XY: 0.00229 AC XY: 310 AN XY: 135650

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000662 AC: 968 AN: 1461168 Hom.: 19 Cov.: 31 AF XY: 0.000557 AC XY: 405 AN XY: 726916

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152380 Hom.: 2 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74518

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.00220

ExAC AF: 0.00252 AC: 306

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.;T;T;T;.;.;T;.
Eigen	Benign	0.036
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;D;T;D;D;.;D;D;D;D;D
MetaRNN	Benign	0.0045	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;M;M;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N;D;D;D;N;N;N;D;D;N;D
REVEL	Benign	0.23
Sift	Benign	0.074	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;D;D;T;T;T;T;T;T;T;D
Polyphen		0.51	P;.;.;.;.;P;P;.;.;.;.
Vest4		0.42
MVP		0.41
MPC		0.44
ClinPred		0.056	T
GERP RS		5.4
Varity_R		0.50
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs184655220; hg19: chr15-75641392;