rs28448386

Variant names:

• chr16-22533848-G-C
• rs28448386
• NM_001395849.1:c.865G>C

Variant summary

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

The NM_001395849.1(NPIPB5):​c.865G>C​(p.Val289Leu) 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.077 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPB5 NM_001395849.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.86
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019716918).
• BP6: Variant 16-22533848-G-C is Benign according to our data. Variant chr16-22533848-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2342066.Status of the report is criteria_provided_single_submitter, 1 stars.

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.865G>C	p.Val289Leu	missense	Exon 7 of 7	NP_001382778.1	A8MRT5
	NPIPB5	NM_001135865.3		c.865G>C	p.Val289Leu	missense	Exon 9 of 9	NP_001129337.1	A8MRT5
	NPIPB5	NM_001395850.1		c.865G>C	p.Val289Leu	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.865G>C	p.Val289Leu	missense	Exon 7 of 7	ENSP00000440703.1	A8MRT5
	NPIPB5	ENST00000528249.5	TSL:1	c.865G>C	p.Val289Leu	missense	Exon 7 of 7	ENSP00000431553.1	E9PKP1
	NPIPB5	ENST00000517539.6	TSL:5	c.865G>C	p.Val289Leu	missense	Exon 8 of 8	ENSP00000430633.1	A8MRT5

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 39 AN: 2938 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00943

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0526

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.415 AC: 568 AN: 1368 AF XY: 0.406

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.439

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.432

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0770 AC: 11913 AN: 154812 Hom.: 0 Cov.: 0 AF XY: 0.0719 AC XY: 6081 AN XY: 84632

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

African (AFR) AF: 0.0780 AC: 383 AN: 4912

American (AMR) AF: 0.122 AC: 851 AN: 6958

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 434 AN: 4638

East Asian (EAS) AF: 0.0728 AC: 856 AN: 11754

South Asian (SAS) AF: 0.0856 AC: 1385 AN: 16182

European-Finnish (FIN) AF: 0.0291 AC: 369 AN: 12676

Middle Eastern (MID) AF: 0.0695 AC: 51 AN: 734

European-Non Finnish (NFE) AF: 0.0775 AC: 6834 AN: 88200

Other (OTH) AF: 0.0856 AC: 750 AN: 8758

⚠️ 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: 0.0132 AC: 39 AN: 2962 Hom.: 0 Cov.: 0 AF XY: 0.0145 AC XY: 22 AN XY: 1514

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

African (AFR) AF: 0.00924 AC: 10 AN: 1082

American (AMR) AF: 0.0137 AC: 5 AN: 364

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 2 AN: 78

East Asian (EAS) AF: 0.00 AC: 0 AN: 76

South Asian (SAS) AF: 0.0526 AC: 2 AN: 38

European-Finnish (FIN) AF: 0.0282 AC: 4 AN: 142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 12

European-Non Finnish (NFE) AF: 0.0140 AC: 16 AN: 1142

Other (OTH) AF: 0.00 AC: 0 AN: 20

⚠️ 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: 0.175 Hom.: 0

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	0.27
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.15
DANN	Benign	0.23
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.94	T
PhyloP100		-1.9
PROVEAN	Benign	0.67	N
REVEL	Benign	0.017
Sift	Benign	0.77	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.071
MutPred		0.37		Gain of catalytic residue at V289 (P = 0.0218)
ClinPred		0.0015	T
Varity_R		0.097
gMVP		0.0049
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: rs28448386; hg19: chr16-22545169;