1-108465287-C-T

Position:

chr1-108465287-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001143988.2(NBPF6):c.1523C>T(p.Thr508Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,192,458 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00099 ( 33 hom., cov: 14)

Exomes 𝑓: 0.0011 ( 370 hom. )

Consequence

NBPF6
NM_001143988.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0880

Variant links:

Genes affected

NBPF6 (HGNC:31988): (NBPF member 6) 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. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2013]

NBPF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01127547).

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBPF6	NM_001143988.2 linkuse as main transcript	c.1523C>T	p.Thr508Ile	missense_variant	13/15	ENST00000495380.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBPF6	ENST00000495380.7 linkuse as main transcript	c.1523C>T	p.Thr508Ile	missense_variant	13/15	5	NM_001143988.2		Q5VWK0-1
NBPF6	ENST00000531446.2 linkuse as main transcript	c.1610C>T	p.Thr537Ile	missense_variant	14/14	1
NBPF6	ENST00000370040.7 linkuse as main transcript	c.1610C>T	p.Thr537Ile	missense_variant	14/16	5		P1	Q5VWK0-2

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

106

AN:

106830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000566

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000265

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00278

GnomAD3 exomes

AF:

0.000898

AC:

110

AN:

122444

Hom.:

AF XY:

0.000859

AC XY:

AN XY:

65200

show subpopulations

Gnomad AFR exome

AF:

0.000183

Gnomad AMR exome

AF:

0.000338

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000775

Gnomad FIN exome

AF:

0.000664

Gnomad NFE exome

AF:

0.00171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00108

AC:

1176

AN:

1085562

Hom.:

370

Cov.:

AF XY:

0.00113

AC XY:

609

AN XY:

536578

show subpopulations

Gnomad4 AFR exome

AF:

0.000130

Gnomad4 AMR exome

AF:

0.000845

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000775

Gnomad4 FIN exome

AF:

0.000427

Gnomad4 NFE exome

AF:

0.00119

Gnomad4 OTH exome

AF:

0.00196

GnomAD4 genome

AF:

0.000992

AC:

106

AN:

106896

Hom.:

Cov.:

AF XY:

0.000982

AC XY:

AN XY:

51950

show subpopulations

Gnomad4 AFR

AF:

0.000564

Gnomad4 AMR

AF:

0.00125

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000265

Gnomad4 NFE

AF:

0.00143

Gnomad4 OTH

AF:

0.00274

Alfa

AF:

0.000538

Hom.:

ExAC

AF:

0.000535

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1610C>T (p.T537I) alteration is located in exon 14 (coding exon 13) of the NBPF6 gene. This alteration results from a C to T substitution at nucleotide position 1610, causing the threonine (T) at amino acid position 537 to be replaced by an isoleucine (I). 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

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.57

T;T;T

M_CAP

Benign

0.0010

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.31

T;T;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.11

MutPred

0.20

.;Loss of disorder (P = 0.0373);.;

MVP

0.17

ClinPred

0.035

GERP RS

-1.5

Varity_R

0.052

gMVP

0.0033

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over