1-16587065-C-G

Variant names:

• chr1-16587065-C-G
• rs79359767
• NM_001405666.3:c.763G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001405666.3(NBPF1):​c.763G>C​(p.Val255Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00008 in 150,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF1 NM_001405666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.906
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044286072).

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.763G>C	p.Val255Leu	missense	Exon 11 of 27	NP_001392595.1	A0AAG2UYR2
	NBPF1	NM_001405667.2		c.763G>C	p.Val255Leu	missense	Exon 11 of 29	NP_001392596.1
	NBPF1	NM_001405680.2		c.763G>C	p.Val255Leu	missense	Exon 11 of 29	NP_001392609.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBPF1	ENST00000430580.6	TSL:5	c.763G>C	p.Val255Leu	missense	Exon 11 of 29	ENSP00000474456.1	Q3BBV0-2
	NBPF1	ENST00000392963.5	TSL:5	n.176-4307G>C		intron	N/A	ENSP00000473795.1	S4R2Z6

Frequencies

GnomAD3 genomes AF: 0.0000800 AC: 12 AN: 149980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249924 AF XY: 0.00000738

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000146 AC: 21 AN: 1434756 Hom.: 1 Cov.: 31 AF XY: 0.0000140 AC XY: 10 AN XY: 715020

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

African (AFR) AF: 0.000516 AC: 17 AN: 32916

American (AMR) AF: 0.0000224 AC: 1 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 85582

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1087986

Other (OTH) AF: 0.0000168 AC: 1 AN: 59388

⚠️ 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 AF: 0.0000800 AC: 12 AN: 150090 Hom.: 0 Cov.: 32 AF XY: 0.0000818 AC XY: 6 AN XY: 73388

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

African (AFR) AF: 0.000299 AC: 12 AN: 40178

American (AMR) AF: 0.00 AC: 0 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67580

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000330 AC: 4

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	Benign	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.046
DANN	Benign	0.43
FATHMM_MKL	Benign	0.00012	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.044	T
PhyloP100		-0.91
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.60	T
Vest4		0.040
MVP		0.092
gMVP		0.017
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79359767; hg19: chr1-16913560; COSMIC: COSV67427116;