1-146069650-T-A

Variant names:

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

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>T​(p.Tyr3568Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,393,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/8 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: not found (cov: 18)
  • Exomes 𝑓: 0.0000043 (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=0.10990211).

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>T	p.Tyr3568Phe	missense	Exon 86 of 90	NP_001289300.1	Q6P3W6
	NBPF10	NM_001039703.6		c.10196A>T	p.Tyr3399Phe	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>T	p.Tyr3568Phe	missense	Exon 86 of 90	ENSP00000463957.6	Q6P3W6

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244410 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

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: 0.00000431 AC: 6 AN: 1393262 Hom.: 0 Cov.: 29 AF XY: 0.00000431 AC XY: 3 AN XY: 696086

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

American (AMR) AF: 0.0000227 AC: 1 AN: 44098

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00000380 AC: 4 AN: 1053476

Other (OTH) AF: 0.0000174 AC: 1 AN: 57456

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.86
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.11	T
PhyloP100		0.85
Sift4G	Pathogenic	0.0	D
Vest4		0.12
gMVP		0.0028
Mutation Taster		=123/77	disease causing (fs/PTC)

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;