1-21471652-G-A

Position:

• chr1-21471652-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032264.6(NBPF3):​c.530G>A​(p.Arg177His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,612,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NBPF3 NM_032264.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.651

Genes affected

NBPF3 (HGNC:25076): (NBPF member 3) This gene is a member of the neuroblastoma breakpoint family (NBPF) which consists of dozens of recently duplicated genes primarily located in segmental duplications on human chromosome 1. This gene family has experienced its greatest expansion within the human lineage and has expanded, to a lesser extent, among primates in general. Members of this gene family are characterized by tandemly repeated copies of DUF1220 protein domains. DUF1220 copy number variations in human chromosomal region 1q21.1, where most DUF1220 domains are located, have been implicated in a number of developmental and neurogenetic diseases such as microcephaly, macrocephaly, autism, schizophrenia, cognitive disability, congenital heart disease, neuroblastoma, and congenital kidney and urinary tract anomalies. Altered expression of some gene family members is associated with several types of cancer. This gene family contains numerous pseudogenes. [provided by RefSeq, Feb 2013]

NBPF3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020174801).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBPF3	NM_032264.6	c.530G>A	p.Arg177His	missense_variant	5/15	ENST00000318249.10	NP_115640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBPF3	ENST00000318249.10	c.530G>A	p.Arg177His	missense_variant	5/15	1	NM_032264.6	ENSP00000316782.5
NBPF3	ENST00000434838.6	n.*1118G>A		non_coding_transcript_exon_variant	9/19	5		ENSP00000391865.2
NBPF3	ENST00000434838.6	n.*1118G>A		3_prime_UTR_variant	9/19	5		ENSP00000391865.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151954 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251188 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135768

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000159 AC: 233 AN: 1460836 Hom.: 0 Cov.: 34 AF XY: 0.000140 AC XY: 102 AN XY: 726760

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152070 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74346

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.530G>A (p.R177H) alteration is located in exon 5 (coding exon 4) of the NBPF3 gene. This alteration results from a G to A substitution at nucleotide position 530, causing the arginine (R) at amino acid position 177 to be replaced by a histidine (H). 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	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.0
DANN	Benign	0.27
DEOGEN2	Benign	0.0024	.;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00063	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.00091	T
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.13	.;N;N;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N;N;N;.
REVEL	Benign	0.026
Sift	Benign	0.34	T;T;T;.
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.29, 1.0	.;B;D;.
Vest4		0.052
MVP		0.19
MPC		0.13
ClinPred		0.0040	T
GERP RS		-2.3
Varity_R		0.026
gMVP		0.065

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369523655; hg19: chr1-21798145;