rs1276946311

Variant names:

• chr13-32522256-C-G
• rs1276946311
• NM_014887.3:c.1399G>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32522256-C-G
• chr13-32522256-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014887.3(N4BP2L2):​c.1399G>C​(p.Asp467His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,380,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. D467N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: N4BP2L2 NM_014887.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.989
• Publications: 0 publications found

Genes affected

N4BP2L2 (HGNC:26916): (NEDD4 binding protein 2 like 2) Enables enzyme binding activity. Involved in negative regulation of hematopoietic stem cell differentiation and positive regulation of hematopoietic stem cell proliferation. Located in nucleus. Part of transcription repressor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17147213).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014887.3. 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
	N4BP2L2	NM_014887.3	MANE Select	c.1399G>C	p.Asp467His	missense	Exon 4 of 6	NP_055702.1	Q92802-1
	N4BP2L2	NM_001320836.3		c.1399G>C	p.Asp467His	missense	Exon 4 of 10	NP_001307765.1
	N4BP2L2	NM_001387001.1		c.1399G>C	p.Asp467His	missense	Exon 4 of 10	NP_001373930.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	N4BP2L2	ENST00000267068.6	TSL:1 MANE Select	c.1399G>C	p.Asp467His	missense	Exon 4 of 6	ENSP00000267068.3	Q92802-1
	N4BP2L2	ENST00000503814.2	TSL:1	n.3793G>C		non_coding_transcript_exon	Exon 1 of 2
	N4BP2L2	ENST00000674422.1		c.1399G>C	p.Asp467His	missense	Exon 5 of 8	ENSP00000501390.1	A0A6I8PU16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1380344 Hom.: 0 Cov.: 26 AF XY: 0.00000438 AC XY: 3 AN XY: 684904

African (AFR) AF: 0.00 AC: 0 AN: 29780

American (AMR) AF: 0.00 AC: 0 AN: 30878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24014

East Asian (EAS) AF: 0.00 AC: 0 AN: 37556

South Asian (SAS) AF: 0.0000143 AC: 1 AN: 69820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073810

Other (OTH) AF: 0.0000350 AC: 2 AN: 57090

GnomAD4 genome Cov.: 32

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	0.23
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N
PhyloP100		0.99
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.062
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.014	D
Polyphen		0.062	B
Vest4		0.28
MutPred		0.25		Gain of catalytic residue at R26 (P = 6e-04)
MVP		0.67
MPC		0.12
ClinPred		0.66	D
GERP RS		0.39
Varity_R		0.11
gMVP		0.43
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1276946311; hg19: chr13-33096393;