1-16591854-C-G

Variant names:

• chr1-16591854-C-G
• rs751433217
• NM_001405666.3:c.168G>C

Variant summary

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

The NM_001405666.3(NBPF1):​c.168G>C​(p.Lys56Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000072 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBPF1 NM_001405666.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.810
• Publications: 1 publications found

Genes affected

NBPF1 (HGNC:26088): (NBPF member 1) 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. [provided by RefSeq, Apr 2013]

ENSG00000271732 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02027914).
• BP6: Variant 1-16591854-C-G is Benign according to our data. Variant chr1-16591854-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2213849.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001405666.3. 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
	NBPF1	NM_001405666.3	MANE Select	c.168G>C	p.Lys56Asn	missense	Exon 7 of 27	NP_001392595.1	A0AAG2UYR2
	NBPF1	NM_001405667.2		c.168G>C	p.Lys56Asn	missense	Exon 7 of 29	NP_001392596.1
	NBPF1	NM_001405680.2		c.168G>C	p.Lys56Asn	missense	Exon 7 of 29	NP_001392609.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBPF1	ENST00000430580.6	TSL:5	c.168G>C	p.Lys56Asn	missense	Exon 7 of 29	ENSP00000474456.1	Q3BBV0-2
	NBPF1	ENST00000392963.5	TSL:5	n.168G>C		non_coding_transcript_exon	Exon 4 of 19	ENSP00000473795.1	S4R2Z6
	ENSG00000271732	ENST00000607700.2	TSL:6	n.137+27C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000359 AC: 53 AN: 147458 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00286

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000746

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247946 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000724 AC: 94 AN: 1298820 Hom.: 0 Cov.: 23 AF XY: 0.0000703 AC XY: 46 AN XY: 654196

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

African (AFR) AF: 0.000100 AC: 3 AN: 29992

American (AMR) AF: 0.000406 AC: 18 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25008

East Asian (EAS) AF: 0.000570 AC: 22 AN: 38608

South Asian (SAS) AF: 0.000205 AC: 17 AN: 82890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4046

European-Non Finnish (NFE) AF: 0.0000329 AC: 32 AN: 971254

Other (OTH) AF: 0.0000364 AC: 2 AN: 54882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000359 AC: 53 AN: 147570 Hom.: 0 Cov.: 24 AF XY: 0.000418 AC XY: 30 AN XY: 71778

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

African (AFR) AF: 0.0000760 AC: 3 AN: 39448

American (AMR) AF: 0.00286 AC: 42 AN: 14706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.000395 AC: 2 AN: 5058

South Asian (SAS) AF: 0.000222 AC: 1 AN: 4502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000746 AC: 5 AN: 67058

Other (OTH) AF: 0.00 AC: 0 AN: 2034

⚠️ 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: 0.0000792 Hom.: 0

ExAC AF: 0.0000742 AC: 9

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.066
DANN	Benign	0.37
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.020	T
PhyloP100		-0.81
PrimateAI	Uncertain	0.57	T
Sift4G	Benign	0.41	T
Vest4		0.25
MVP		0.29
GERP RS		-1.1
gMVP		0.034
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: rs751433217; hg19: chr1-16918349; COSMIC: COSV105332887; COSMIC: COSV105332887;