1-21471769-A-C

Position:

• chr1-21471769-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032264.6(NBPF3):​c.647A>C​(p.Gln216Pro) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NBPF3 NM_032264.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0990

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16799861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBPF3	NM_032264.6	c.647A>C	p.Gln216Pro	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.647A>C	p.Gln216Pro	missense_variant	5/15	1	NM_032264.6	ENSP00000316782.5
NBPF3	ENST00000434838.6	n.*1235A>C		non_coding_transcript_exon_variant	9/19	5		ENSP00000391865.2
NBPF3	ENST00000434838.6	n.*1235A>C		3_prime_UTR_variant	9/19	5		ENSP00000391865.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

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

Jan 25, 2024

The c.647A>C (p.Q216P) alteration is located in exon 5 (coding exon 4) of the NBPF3 gene. This alteration results from a A to C substitution at nucleotide position 647, causing the glutamine (Q) at amino acid position 216 to be replaced by a proline (P). 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	0.34
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	6.1
DANN	Benign	0.90
DEOGEN2	Benign	0.090	.;.;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	.;L;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D;D;D;.
REVEL	Benign	0.15
Sift	Benign	0.13	T;T;T;.
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.99, 0.97	.;D;D;.
Vest4		0.28
MutPred		0.18		.;Gain of glycosylation at Q216 (P = 0.0384);Gain of glycosylation at Q216 (P = 0.0384);.;
MVP		0.38
MPC		0.15
ClinPred		0.29	T
GERP RS		-1.5
Varity_R		0.17
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-21798262;