1-16587113-T-C

Position:

• chr1-16587113-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001405667.2(NBPF1):​c.715A>G​(p.Thr239Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (29 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF1 NM_001405667.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.924

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02090326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBPF1	NM_001405667.2	c.715A>G	p.Thr239Ala	missense_variant	11/29		NP_001392596.1
NBPF1	NM_001405680.2	c.715A>G	p.Thr239Ala	missense_variant	11/29		NP_001392609.1
NBPF1	NM_001405681.2	c.715A>G	p.Thr239Ala	missense_variant	11/29		NP_001392610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBPF1	ENST00000430580.6	c.715A>G	p.Thr239Ala	missense_variant	11/29	5		ENSP00000474456.1
NBPF1	ENST00000392963.5	n.176-4355A>G		intron_variant		5		ENSP00000473795.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 307 AN: 136352 Hom.: 2 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.000625

Gnomad EAS AF: 0.00966

Gnomad SAS AF: 0.00495

Gnomad FIN AF: 0.000296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00325

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 248820 Hom.: 2 AF XY: 0.000148 AC XY: 20 AN XY: 134764

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.000298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000314 AC: 455 AN: 1449196 Hom.: 29 Cov.: 43 AF XY: 0.000311 AC XY: 224 AN XY: 720954

Gnomad4 AFR exome AF: 0.000578

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.000193

Gnomad4 EAS exome AF: 0.000847

Gnomad4 SAS exome AF: 0.000386

Gnomad4 FIN exome AF: 0.000265

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.000352

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00226 AC: 308 AN: 136470 Hom.: 2 Cov.: 32 AF XY: 0.00253 AC XY: 169 AN XY: 66918

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.00145

Gnomad4 ASJ AF: 0.000625

Gnomad4 EAS AF: 0.00968

Gnomad4 SAS AF: 0.00495

Gnomad4 FIN AF: 0.000296

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00321

Alfa AF: 0.0197 Hom.: 0

ExAC AF: 0.0000165 AC: 2

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

Aug 10, 2021

The c.715A>G (p.T239A) alteration is located in exon 11 (coding exon 5) of the NBPF1 gene. This alteration results from a A to G substitution at nucleotide position 715, causing the threonine (T) at amino acid position 239 to be replaced by an alanine (A). 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	-0.59	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0060
DANN	Benign	0.40
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.096	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.021	T;T
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.47	T;T
Vest4		0.060
MVP		0.061
gMVP		0.021

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: rs531297430; hg19: chr1-16913608; COSMIC: COSV67429519;