4-177310080-G-T

Variant names:

• chr4-177310080-G-T
• rs1262043356
• NM_018248.3:c.127G>T

Variant summary

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

The NM_018248.3(NEIL3):​c.127G>T​(p.Ala43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,443,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NEIL3 NM_018248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.822

Genes affected

NEIL3 (HGNC:24573): (nei like DNA glycosylase 3) NEIL3 belongs to a class of DNA glycosylases homologous to the bacterial Fpg/Nei family. These glycosylases initiate the first step in base excision repair by cleaving bases damaged by reactive oxygen species and introducing a DNA strand break via the associated lyase reaction (Bandaru et al., 2002 [PubMed 12509226]).[supplied by OMIM, Mar 2008]

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=0.082885265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEIL3	NM_018248.3	c.127G>T	p.Ala43Ser	missense_variant	Exon 1 of 10	ENST00000264596.4	NP_060718.3
NEIL3	XM_047415894.1	c.127G>T	p.Ala43Ser	missense_variant	Exon 1 of 12		XP_047271850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEIL3	ENST00000264596.4	c.127G>T	p.Ala43Ser	missense_variant	Exon 1 of 10	1	NM_018248.3	ENSP00000264596.3
NEIL3	ENST00000513321.1	n.127G>T		non_coding_transcript_exon_variant	Exon 1 of 4	1		ENSP00000424735.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1443282 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

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

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127G>T (p.A43S) alteration is located in exon 1 (coding exon 1) of the NEIL3 gene. This alteration results from a G to T substitution at nucleotide position 127, causing the alanine (A) at amino acid position 43 to be replaced by a serine (S). 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	0.090
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.1
DANN	Benign	0.92
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.028
Sift	Benign	0.18	T
Sift4G	Benign	0.47	T
Polyphen		0.060	B
Vest4		0.081
MutPred		0.35		Gain of disorder (P = 0.0278);
MVP		0.16
MPC		0.14
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.069
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs1262043356; hg19: chr4-178231234;