chr1-16589999-A-C

Position:

• chr1-16589999-A-C

Variant summary

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

The NM_001405667.2(NBPF1):​c.178T>G​(p.Tyr60Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,574,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 44)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: NBPF1 NM_001405667.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.706

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBPF1	NM_001405667.2	c.178T>G	p.Tyr60Asp	missense_variant, splice_region_variant	8/29		NP_001392596.1
NBPF1	NM_001405680.2	c.178T>G	p.Tyr60Asp	missense_variant, splice_region_variant	8/29		NP_001392609.1
NBPF1	NM_001405681.2	c.178T>G	p.Tyr60Asp	missense_variant, splice_region_variant	8/29		NP_001392610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBPF1	ENST00000430580.6	c.178T>G	p.Tyr60Asp	missense_variant, splice_region_variant	8/29	5		ENSP00000474456.1
NBPF1	ENST00000392963.5	n.175+1848T>G		intron_variant		5		ENSP00000473795.1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 151746 Hom.: 0 Cov.: 44

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00108 AC: 266 AN: 246512 Hom.: 0 AF XY: 0.00111 AC XY: 149 AN XY: 134064

Gnomad AFR exome AF: 0.000398

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.000503

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000428

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00182 AC: 2593 AN: 1422180 Hom.: 0 Cov.: 33 AF XY: 0.00176 AC XY: 1249 AN XY: 709678

Gnomad4 AFR exome AF: 0.000307

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.000540

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000445

Gnomad4 FIN exome AF: 0.000323

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00103 AC: 157 AN: 151862 Hom.: 0 Cov.: 44 AF XY: 0.000862 AC XY: 64 AN XY: 74230

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000720 Hom.: 0

ESP6500AA AF: 0.000859 AC: 3

ESP6500EA AF: 0.00196 AC: 15

ExAC AF: 0.00127 AC: 153

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

Mar 28, 2024

The c.178T>G (p.Y60D) alteration is located in exon 8 (coding exon 2) of the NBPF1 gene. This alteration results from a T to G substitution at nucleotide position 178, causing the tyrosine (Y) at amino acid position 60 to be replaced by an aspartic acid (D). 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
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	17
DANN	Benign	0.54
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.0064	T;T
PrimateAI	Uncertain	0.57	T
Sift4G	Benign	0.20	T;T
Vest4		0.31
MVP		0.30
GERP RS		0.55
gMVP		0.033

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs371668692; hg19: chr1-16916494;