chr1-146069650-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001302371.3(NBPF10):​c.10703A>C​(p.Tyr3568Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 18)
  • Exomes 𝑓: 0.0015 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF10 NM_001302371.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06441647).
• BP6: Variant 1-146069650-T-G is Benign according to our data. Variant chr1-146069650-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2639103.Status of the report is criteria_provided_single_submitter, 1 stars.

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>C	p.Tyr3568Ser	missense	Exon 86 of 90	NP_001289300.1	Q6P3W6
	NBPF10	NM_001039703.6		c.10196A>C	p.Tyr3399Ser	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>C	p.Tyr3568Ser	missense	Exon 86 of 90	ENSP00000463957.6	Q6P3W6

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 139 AN: 124224 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000259

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00122

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.000702

Gnomad OTH AF: 0.00361

GnomAD2 exomes AF: 0.00126 AC: 307 AN: 244410 AF XY: 0.00120

Gnomad AFR exome AF: 0.00888

Gnomad AMR exome AF: 0.000498

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000844

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00153 AC: 2135 AN: 1392736 Hom.: 7 Cov.: 29 AF XY: 0.00147 AC XY: 1025 AN XY: 695834

African (AFR) AF: 0.00839 AC: 267 AN: 31818

American (AMR) AF: 0.000499 AC: 22 AN: 44092

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25438

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.000856 AC: 73 AN: 85276

European-Finnish (FIN) AF: 0.0000960 AC: 5 AN: 52086

Middle Eastern (MID) AF: 0.000741 AC: 3 AN: 4048

European-Non Finnish (NFE) AF: 0.00153 AC: 1616 AN: 1053138

Other (OTH) AF: 0.00258 AC: 148 AN: 57426

GnomAD4 genome AF: 0.00114 AC: 142 AN: 124308 Hom.: 1 Cov.: 18 AF XY: 0.00118 AC XY: 71 AN XY: 60380

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

African (AFR) AF: 0.00263 AC: 87 AN: 33120

American (AMR) AF: 0.000259 AC: 3 AN: 11604

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4766

South Asian (SAS) AF: 0.00122 AC: 5 AN: 4090

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

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.000702 AC: 40 AN: 56992

Other (OTH) AF: 0.00357 AC: 6 AN: 1680

⚠️ 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: 0.000595 Hom.: 0

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.9
DANN	Benign	0.61
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.064	T
PhyloP100		0.85
Sift4G	Pathogenic	0.0	D
Vest4		0.21
Varity_R		0.15
gMVP		0.0088
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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; COSMIC: COSV61662175;