1-108450734-A-T

Position:

• chr1-108450734-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001143988.2(NBPF6):​c.133A>T​(p.Thr45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 16)
  • Exomes 𝑓: 0.0000047 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF6 NM_001143988.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.255

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034740776).
• BP6: Variant 1-108450734-A-T is Benign according to our data. Variant chr1-108450734-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2410758.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBPF6	NM_001143988.2	c.133A>T	p.Thr45Ser	missense_variant	2/15	ENST00000495380.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBPF6	ENST00000495380.7	c.133A>T	p.Thr45Ser	missense_variant	2/15	5	NM_001143988.2
NBPF6	ENST00000531446.2	c.133A>T	p.Thr45Ser	missense_variant	2/14	1
NBPF6	ENST00000370040.7	c.133A>T	p.Thr45Ser	missense_variant	2/16	5		P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5 AN: 113354 Hom.: 0 Cov.: 16 FAILED QC

Gnomad AFR AF: 0.00

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: 0.000102

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000468 AC: 5 AN: 1068486 Hom.: 0 Cov.: 17 AF XY: 0.00000560 AC XY: 3 AN XY: 535652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000280

Gnomad4 FIN exome AF: 0.0000435

Gnomad4 NFE exome AF: 0.00000127

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000441 AC: 5 AN: 113354 Hom.: 0 Cov.: 16 AF XY: 0.0000549 AC XY: 3 AN XY: 54632

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000102

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.040
DANN	Benign	0.13
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.00017	N
LIST_S2	Benign	0.032	T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.070	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.71	T;T;T
Sift4G	Benign	0.96	T;T;T
Polyphen		0.41	.;B;.
Vest4		0.043
MutPred		0.26		Gain of disorder (P = 0.0546);Gain of disorder (P = 0.0546);Gain of disorder (P = 0.0546);
MVP		0.11
ClinPred		0.11	T
GERP RS		-3.1
Varity_R		0.034
gMVP		0.011

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: rs1652796434; hg19: chr1-108993356;