chr1-16583694-A-T

Position:

• chr1-16583694-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001405667.2(NBPF1):​c.991T>A​(p.Tyr331Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000723 in 152,212 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 81)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF1 NM_001405667.2 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.842

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031454176).
• BP6: Variant 1-16583694-A-T is Benign according to our data. Variant chr1-16583694-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2638364.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBPF1	NM_001405667.2	c.991T>A	p.Tyr331Asn	missense_variant, splice_region_variant	13/29		NP_001392596.1
NBPF1	NM_001405680.2	c.991T>A	p.Tyr331Asn	missense_variant, splice_region_variant	13/29		NP_001392609.1
NBPF1	NM_001405681.2	c.991T>A	p.Tyr331Asn	missense_variant, splice_region_variant	13/29		NP_001392610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBPF1	ENST00000430580.6	c.991T>A	p.Tyr331Asn	missense_variant, splice_region_variant	13/29	5		ENSP00000474456.1
NBPF1	ENST00000392963.5	n.176-936T>A		intron_variant		5		ENSP00000473795.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152212 Hom.: 0 Cov.: 81

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000569 AC: 129 AN: 226718 Hom.: 18 AF XY: 0.000573 AC XY: 71 AN XY: 123934

Gnomad AFR exome AF: 0.000211

Gnomad AMR exome AF: 0.0000942

Gnomad ASJ exome AF: 0.00138

Gnomad EAS exome AF: 0.0000650

Gnomad SAS exome AF: 0.000172

Gnomad FIN exome AF: 0.000346

Gnomad NFE exome AF: 0.000895

Gnomad OTH exome AF: 0.000895

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000100 AC: 146 AN: 1459856 Hom.: 0 Cov.: 52 AF XY: 0.0000991 AC XY: 72 AN XY: 726250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152212 Hom.: 0 Cov.: 81 AF XY: 0.0000538 AC XY: 4 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000484 Hom.: 0

ExAC AF: 0.000663 AC: 77

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

NBPF1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.59
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.031	T;T
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.53	T;T
Vest4		0.34
MVP		0.29
GERP RS		0.39
gMVP		0.022

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: rs745730223; hg19: chr1-16910189;