1-146069650-T-C

Variant names:

• chr1-146069650-T-C
• rs587638297
• NM_001302371.3:c.10703A>G

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.10703A>G​(p.Tyr3568Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000857 in 1,517,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y3568S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000080 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: NBPF10 NM_001302371.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.846
• 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=0.13309789).

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.10703A>G	p.Tyr3568Cys	missense	Exon 86 of 90	NP_001289300.1	Q6P3W6
	NBPF10	NM_001039703.6		c.10196A>G	p.Tyr3399Cys	missense	Exon 82 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.10703A>G	p.Tyr3568Cys	missense	Exon 86 of 90	ENSP00000463957.6	Q6P3W6

Frequencies

GnomAD3 genomes AF: 0.00000804 AC: 1 AN: 124332 Hom.: 0 Cov.: 18

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: 0.0000175

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244410 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000861 AC: 12 AN: 1393264 Hom.: 0 Cov.: 29 AF XY: 0.0000115 AC XY: 8 AN XY: 696086

African (AFR) AF: 0.00 AC: 0 AN: 31904

American (AMR) AF: 0.00 AC: 0 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25438

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39414

South Asian (SAS) AF: 0.00 AC: 0 AN: 85338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4050

European-Non Finnish (NFE) AF: 0.0000104 AC: 11 AN: 1053476

Other (OTH) AF: 0.00 AC: 0 AN: 57458

GnomAD4 genome AF: 0.00000804 AC: 1 AN: 124332 Hom.: 0 Cov.: 18 AF XY: 0.0000166 AC XY: 1 AN XY: 60338

⚠️ 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: 33108

American (AMR) AF: 0.00 AC: 0 AN: 11586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3120

East Asian (EAS) AF: 0.00 AC: 0 AN: 4778

South Asian (SAS) AF: 0.00 AC: 0 AN: 4096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000175 AC: 1 AN: 57026

Other (OTH) AF: 0.00 AC: 0 AN: 1662

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.2
DANN	Benign	0.73
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.13	T
PhyloP100		0.85
Sift4G	Pathogenic	0.0	D
Vest4		0.16
gMVP		0.0079
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs587638297; hg19: chr1-145365352;