1-16589957-C-T

Variant names:

• chr1-16589957-C-T
• rs1316549445
• NM_001405666.3:c.220G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001405666.3(NBPF1):​c.220G>A​(p.Glu74Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 46)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NBPF1 NM_001405666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.884
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077477425).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001405666.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBPF1	NM_001405666.3	MANE Select	c.220G>A	p.Glu74Lys	missense	Exon 8 of 27	NP_001392595.1	A0AAG2UYR2
	NBPF1	NM_001405667.2		c.220G>A	p.Glu74Lys	missense	Exon 8 of 29	NP_001392596.1
	NBPF1	NM_001405680.2		c.220G>A	p.Glu74Lys	missense	Exon 8 of 29	NP_001392609.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBPF1	ENST00000430580.6	TSL:5	c.220G>A	p.Glu74Lys	missense	Exon 8 of 29	ENSP00000474456.1	Q3BBV0-2
	NBPF1	ENST00000392963.5	TSL:5	n.175+1890G>A		intron	N/A	ENSP00000473795.1	S4R2Z6

Frequencies

GnomAD3 genomes Cov.: 46

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246384 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429628 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 712828

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32218

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4266

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085840

Other (OTH) AF: 0.00 AC: 0 AN: 59196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 46

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.3
DANN	Benign	0.25
FATHMM_MKL	Benign	0.00031	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.077	T
PhyloP100		-0.88
PrimateAI	Uncertain	0.58	T
Sift4G	Uncertain	0.049	D
Vest4		0.19
MVP		0.28
GERP RS		-0.95
gMVP		0.051
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1316549445; hg19: chr1-16916452;