16-22533816-C-T

Variant names:

• chr16-22533816-C-T
• rs1409334904
• NM_001395849.1:c.833C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001395849.1(NPIPB5):​c.833C>T​(p.Ala278Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A278E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 5)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPB5 NM_001395849.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.34
• Publications: 0 publications found

Genes affected

NPIPB5 (HGNC:37233): (nuclear pore complex interacting protein family member B5) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LOC105371131 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07623607).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395849.1. 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
	NPIPB5	NM_001395849.1	MANE Select	c.833C>T	p.Ala278Val	missense	Exon 7 of 7	NP_001382778.1	A8MRT5
	NPIPB5	NM_001135865.3		c.833C>T	p.Ala278Val	missense	Exon 9 of 9	NP_001129337.1	A8MRT5
	NPIPB5	NM_001395850.1		c.833C>T	p.Ala278Val	missense	Exon 8 of 8	NP_001382779.1	A8MRT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPIPB5	ENST00000424340.7	TSL:1 MANE Select	c.833C>T	p.Ala278Val	missense	Exon 7 of 7	ENSP00000440703.1	A8MRT5
	NPIPB5	ENST00000528249.5	TSL:1	c.833C>T	p.Ala278Val	missense	Exon 7 of 7	ENSP00000431553.1	E9PKP1
	NPIPB5	ENST00000517539.6	TSL:5	c.833C>T	p.Ala278Val	missense	Exon 8 of 8	ENSP00000430633.1	A8MRT5

Frequencies

GnomAD3 genomes AF: 0.0000535 AC: 1 AN: 18696 Hom.: 0 Cov.: 5

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: 0.000142

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000301 AC: 1 AN: 33176 AF XY: 0.0000579

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000216

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: 0.000118 AC: 53 AN: 450414 Hom.: 0 Cov.: 0 AF XY: 0.000113 AC XY: 27 AN XY: 238990

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

African (AFR) AF: 0.00 AC: 0 AN: 13188

American (AMR) AF: 0.0000450 AC: 1 AN: 22242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14156

East Asian (EAS) AF: 0.000326 AC: 10 AN: 30720

South Asian (SAS) AF: 0.0000639 AC: 3 AN: 46942

European-Finnish (FIN) AF: 0.0000339 AC: 1 AN: 29460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1976

European-Non Finnish (NFE) AF: 0.000132 AC: 35 AN: 265824

Other (OTH) AF: 0.000116 AC: 3 AN: 25906

⚠️ 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: 0.0000535 AC: 1 AN: 18696 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 9096

⚠️ 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: 7266

American (AMR) AF: 0.00 AC: 0 AN: 1782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 460

East Asian (EAS) AF: 0.00 AC: 0 AN: 448

South Asian (SAS) AF: 0.00 AC: 0 AN: 374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.000142 AC: 1 AN: 7028

Other (OTH) AF: 0.00 AC: 0 AN: 174

⚠️ 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

ClinVar submissions

Significance: Uncertain significance

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	0.31
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.7
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.3
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.078
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.60	P
Vest4		0.054
MutPred		0.58		Loss of relative solvent accessibility (P = 0.0404)
MVP		0.040
ClinPred		0.088	T
Varity_R		0.040
gMVP		0.0092

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: rs1409334904; hg19: chr16-22545137;