1-16583686-C-G

Variant names:

• chr1-16583686-C-G
• rs201327573
• ENST00000430580.6:c.999G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001405667.2(NBPF1):​c.999G>C​(p.Glu333Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 130,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (0 hom., cov: 80)
  • Exomes 𝑓: 0.0060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF1 NM_001405667.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.576

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038354695).
• BP6: Variant 1-16583686-C-G is Benign according to our data. Variant chr1-16583686-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2353530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBPF1	NM_001405667.2	c.999G>C	p.Glu333Asp	missense_variant	Exon 13 of 29		NP_001392596.1
NBPF1	NM_001405680.2	c.999G>C	p.Glu333Asp	missense_variant	Exon 13 of 29		NP_001392609.1
NBPF1	NM_001405681.2	c.999G>C	p.Glu333Asp	missense_variant	Exon 13 of 29		NP_001392610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBPF1	ENST00000430580.6	c.999G>C	p.Glu333Asp	missense_variant	Exon 13 of 29	5		ENSP00000474456.1
NBPF1	ENST00000392963.5	n.176-928G>C		intron_variant	Intron 4 of 18	5		ENSP00000473795.1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 3661 AN: 130334 Hom.: 0 Cov.: 80

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00241

Gnomad SAS AF: 0.000846

Gnomad FIN AF: 0.00568

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00102 AC: 230 AN: 224436 Hom.: 0 AF XY: 0.000910 AC XY: 112 AN XY: 123026

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000859

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000132

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00219

Gnomad NFE exome AF: 0.0000674

Gnomad OTH exome AF: 0.000899

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00605 AC: 7915 AN: 1309254 Hom.: 0 Cov.: 68 AF XY: 0.00551 AC XY: 3608 AN XY: 654412

Gnomad4 AFR exome AF: 0.0938

Gnomad4 AMR exome AF: 0.00709

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.00818

Gnomad4 SAS exome AF: 0.000653

Gnomad4 FIN exome AF: 0.00806

Gnomad4 NFE exome AF: 0.00429

Gnomad4 OTH exome AF: 0.00800

GnomAD4 genome AF: 0.0281 AC: 3667 AN: 130402 Hom.: 0 Cov.: 80 AF XY: 0.0278 AC XY: 1774 AN XY: 63884

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00241

Gnomad4 SAS AF: 0.000846

Gnomad4 FIN AF: 0.00568

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00755 Hom.: 0

ExAC AF: 0.000274 AC: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 06, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.6
DANN	Benign	0.32
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0038	T;T
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	0.55	T;T
Vest4		0.15
MVP		0.37
GERP RS		-0.78
gMVP		0.027

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: rs201327573; hg19: chr1-16910181; COSMIC: COSV67426817;