1-108450665-C-G

Position:

• chr1-108450665-C-G

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.64C>G​(p.Gln22Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 15)
  • Exomes 𝑓: 0.0018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF6 NM_001143988.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28

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=0.003463477).
• BP6: Variant 1-108450665-C-G is Benign according to our data. Variant chr1-108450665-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2348144.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.64C>G	p.Gln22Glu	missense_variant	2/15	ENST00000495380.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBPF6	ENST00000495380.7	c.64C>G	p.Gln22Glu	missense_variant	2/15	5	NM_001143988.2
NBPF6	ENST00000531446.2	c.64C>G	p.Gln22Glu	missense_variant	2/14	1
NBPF6	ENST00000370040.7	c.64C>G	p.Gln22Glu	missense_variant	2/16	5		P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 138 AN: 100416 Hom.: 0 Cov.: 15 FAILED QC

Gnomad AFR AF: 0.000187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000385

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00627

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000376

Gnomad OTH AF: 0.00301

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00181 AC: 1597 AN: 883724 Hom.: 0 Cov.: 13 AF XY: 0.00167 AC XY: 758 AN XY: 453724

Gnomad4 AFR exome AF: 0.0000404

Gnomad4 AMR exome AF: 0.0000547

Gnomad4 ASJ exome AF: 0.0000475

Gnomad4 EAS exome AF: 0.0283

Gnomad4 SAS exome AF: 0.000528

Gnomad4 FIN exome AF: 0.00398

Gnomad4 NFE exome AF: 0.000527

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00136 AC: 137 AN: 100548 Hom.: 0 Cov.: 15 AF XY: 0.00151 AC XY: 73 AN XY: 48420

Gnomad4 AFR AF: 0.000186

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000385

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00627

Gnomad4 NFE AF: 0.000376

Gnomad4 OTH AF: 0.00298

Alfa AF: 0.000678 Hom.: 0

ExAC AF: 0.000450 AC: 3

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

Dec 14, 2021

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	0.088
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0050
DANN	Benign	0.17
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.49	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.43	N;N;N
REVEL	Benign	0.011
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.17
MutPred		0.20		Gain of phosphorylation at S26 (P = 0.1359);Gain of phosphorylation at S26 (P = 0.1359);Gain of phosphorylation at S26 (P = 0.1359);
MVP		0.25
ClinPred		0.0016	T
GERP RS		-3.7
Varity_R		0.032
gMVP		0.0075

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: rs762424223; hg19: chr1-108993287;