4-40102147-G-T

Variant names:

• chr4-40102147-G-T
• rs17511668
• NM_018177.6:c.302G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018177.6(N4BP2):​c.302G>T​(p.Ser101Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,612,696 control chromosomes in the GnomAD database, including 42,341 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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: 𝑓 0.18 (3083 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39258 hom.)
• Consequence: N4BP2 NM_018177.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.161
• Publications: 22 publications found

Genes affected

N4BP2 (HGNC:29851): (NEDD4 binding protein 2) This gene encodes a protein containing a polynucleotide kinase domain (PNK) near the N-terminal region, and a Small MutS Related (Smr) domain near the C-terminal region. The encoded protein can bind to both B-cell leukemia/lymphoma 3 (BCL-3) and neural precursor cell expressed, developmentally downregulated 4, (Nedd4) proteins. This protein binds and hydrolyzes ATP, may function as a 5'-polynucleotide kinase, and has the capacity to be a ubiquitylation substrate. This protein may play a role in transcription-coupled DNA repair or genetic recombination. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039281845).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018177.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	N4BP2	NM_018177.6	MANE Select	c.302G>T	p.Ser101Ile	missense	Exon 4 of 18	NP_060647.2
	N4BP2	NM_001318359.2		c.62G>T	p.Ser21Ile	missense	Exon 5 of 19	NP_001305288.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	N4BP2	ENST00000261435.11	TSL:5 MANE Select	c.302G>T	p.Ser101Ile	missense	Exon 4 of 18	ENSP00000261435.6
	N4BP2	ENST00000511480.5	TSL:1	n.*93G>T		non_coding_transcript_exon	Exon 5 of 19	ENSP00000422436.1
	N4BP2	ENST00000511480.5	TSL:1	n.*93G>T		3_prime_UTR	Exon 5 of 19	ENSP00000422436.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26856 AN: 151968 Hom.: 3079 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.205 AC: 51538 AN: 250830 AF XY: 0.208

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.0318

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.225 AC: 328893 AN: 1460610 Hom.: 39258 Cov.: 32 AF XY: 0.225 AC XY: 163304 AN XY: 726634

African (AFR) AF: 0.0393 AC: 1314 AN: 33456

American (AMR) AF: 0.273 AC: 12147 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4645 AN: 26102

East Asian (EAS) AF: 0.0332 AC: 1316 AN: 39638

South Asian (SAS) AF: 0.187 AC: 16104 AN: 86160

European-Finnish (FIN) AF: 0.250 AC: 13324 AN: 53340

Middle Eastern (MID) AF: 0.185 AC: 1065 AN: 5760

European-Non Finnish (NFE) AF: 0.240 AC: 267077 AN: 1111258

Other (OTH) AF: 0.197 AC: 11901 AN: 60336

GnomAD4 genome AF: 0.177 AC: 26863 AN: 152086 Hom.: 3083 Cov.: 32 AF XY: 0.181 AC XY: 13429 AN XY: 74344

African (AFR) AF: 0.0458 AC: 1901 AN: 41536

American (AMR) AF: 0.256 AC: 3906 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 623 AN: 3466

East Asian (EAS) AF: 0.0255 AC: 132 AN: 5176

South Asian (SAS) AF: 0.179 AC: 862 AN: 4828

European-Finnish (FIN) AF: 0.256 AC: 2697 AN: 10540

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15988 AN: 67946

Other (OTH) AF: 0.175 AC: 368 AN: 2108

Alfa AF: 0.210 Hom.: 14324

Bravo AF: 0.171

TwinsUK AF: 0.243 AC: 902

ALSPAC AF: 0.254 AC: 977

ESP6500AA AF: 0.0486 AC: 214

ESP6500EA AF: 0.230 AC: 1978

ExAC AF: 0.199 AC: 24209

Asia WGS AF: 0.0890 AC: 308 AN: 3478

EpiCase AF: 0.223

EpiControl AF: 0.234

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.054
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		0.34	B
Vest4		0.062
MPC		0.18
ClinPred		0.0092	T
GERP RS		1.3
Varity_R		0.22
gMVP		0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs17511668; hg19: chr4-40103767; COSMIC: COSV107219489; COSMIC: COSV107219489;