1-16581450-G-T

Position:

• chr1-16581450-G-T

Variant summary

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

The NM_001405667.2(NBPF1):​c.1349C>A​(p.Ala450Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 81)
• Consequence: NBPF1 NM_001405667.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.841

Genes affected

NBPF1 (HGNC:26088): (NBPF member 1) 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. Gene copy number variations in the 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, Apr 2013]

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=0.066237986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBPF1	NM_001405667.2	c.1349C>A	p.Ala450Asp	missense_variant	15/29		NP_001392596.1
NBPF1	NM_001405680.2	c.1349C>A	p.Ala450Asp	missense_variant	15/29		NP_001392609.1
NBPF1	NM_001405681.2	c.1349C>A	p.Ala450Asp	missense_variant	15/29		NP_001392610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBPF1	ENST00000430580.6	c.1349C>A	p.Ala450Asp	missense_variant	15/29	5		ENSP00000474456.1
NBPF1	ENST00000392963.5	n.*217C>A		non_coding_transcript_exon_variant	6/19	5		ENSP00000473795.1
NBPF1	ENST00000392963.5	n.*217C>A		3_prime_UTR_variant	6/19	5		ENSP00000473795.1

Frequencies

GnomAD3 genomes Cov.: 81

GnomAD4 exome Cov.: 124

GnomAD4 genome Cov.: 81

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

Oct 06, 2021

The c.1349C>A (p.A450D) alteration is located in exon 15 (coding exon 9) of the NBPF1 gene. This alteration results from a C to A substitution at nucleotide position 1349, causing the alanine (A) at amino acid position 450 to be replaced by an aspartic acid (D). 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
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.9
DANN	Benign	0.55
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.066	T;T
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.57	T;T
Vest4		0.24
MVP		0.18
GERP RS		-1.7
gMVP		0.23

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: rs199840175; hg19: chr1-16907945; COSMIC: COSV55322883;