1-21472920-C-T

Position:

• chr1-21472920-C-T

Variant summary

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

The NM_032264.6(NBPF3):​c.734+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,604,538 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (55 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (41 hom.)
• Consequence: NBPF3 NM_032264.6 splice_region, intron
• Scores: Splicing: ADA: 0.00005099
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-21472920-C-T is Benign according to our data. Variant chr1-21472920-C-T is described in ClinVar as [Benign]. Clinvar id is 789913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2062/152294) while in subpopulation AFR AF= 0.0459 (1908/41548). AF 95% confidence interval is 0.0442. There are 55 homozygotes in gnomad4. There are 947 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBPF3	NM_032264.6	c.734+5C>T		splice_region_variant, intron_variant		ENST00000318249.10	NP_115640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBPF3	ENST00000318249.10	c.734+5C>T		splice_region_variant, intron_variant		1	NM_032264.6	ENSP00000316782.5
NBPF3	ENST00000434838.6	n.*1322+5C>T		splice_region_variant, intron_variant		5		ENSP00000391865.2

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2047 AN: 152176 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00374 AC: 939 AN: 250938 Hom.: 15 AF XY: 0.00290 AC XY: 393 AN XY: 135624

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000556

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00163 AC: 2367 AN: 1452244 Hom.: 41 Cov.: 28 AF XY: 0.00149 AC XY: 1080 AN XY: 723108

Gnomad4 AFR exome AF: 0.0459

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00418

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.0135 AC: 2062 AN: 152294 Hom.: 55 Cov.: 33 AF XY: 0.0127 AC XY: 947 AN XY: 74462

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00270 Hom.: 22

Bravo AF: 0.0148

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.7
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.044
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: rs11584459; hg19: chr1-21799413;