chr1-146126300-C-G

Variant names:

• chr1-146126300-C-G
• rs782443316
• NM_001302371.3:c.1962G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001302371.3(NBPF10):​c.1962G>C​(p.Gln654His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,585,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q654Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: NBPF10 NM_001302371.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.825
• Publications: 0 publications found

Genes affected

NBPF10 (HGNC:31992): (NBPF member 10) 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 results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07782063).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302371.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBPF10	NM_001302371.3	MANE Select	c.1962G>C	p.Gln654His	missense	Exon 14 of 90	NP_001289300.1	Q6P3W6
	NBPF10	NM_001039703.6		c.1962G>C	p.Gln654His	missense	Exon 14 of 86	NP_001034792.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBPF10	ENST00000583866.9	TSL:5 MANE Select	c.1962G>C	p.Gln654His	missense	Exon 14 of 90	ENSP00000463957.6	Q6P3W6
	NBPF10	ENST00000612520.2	TSL:5	c.1853+728G>C		intron	N/A	ENSP00000483006.2	A0A087X002

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151706 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236266 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000312

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1433302 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 714738

African (AFR) AF: 0.00 AC: 0 AN: 32662

American (AMR) AF: 0.0000224 AC: 1 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4180

European-Non Finnish (NFE) AF: 0.00000460 AC: 5 AN: 1087902

Other (OTH) AF: 0.0000168 AC: 1 AN: 59354

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151706 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41174

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.9
DANN	Benign	0.95
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.078	T
PhyloP100		0.82
Sift4G	Uncertain	0.010	D
Vest4		0.092
gMVP		0.046

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782443316; hg19: chr1-145311894;