NM_001395849.1:c.746C>T

Variant names:

• chr16-22533729-C-T
• rs1325942907
• NM_001395849.1:c.746C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001395849.1(NPIPB5):​c.746C>T​(p.Pro249Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPB5 NM_001395849.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.673
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3262322).

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.746C>T	p.Pro249Leu	missense	Exon 7 of 7	NP_001382778.1	A8MRT5
	NPIPB5	NM_001135865.3		c.746C>T	p.Pro249Leu	missense	Exon 9 of 9	NP_001129337.1	A8MRT5
	NPIPB5	NM_001395850.1		c.746C>T	p.Pro249Leu	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.746C>T	p.Pro249Leu	missense	Exon 7 of 7	ENSP00000440703.1	A8MRT5
	NPIPB5	ENST00000528249.5	TSL:1	c.746C>T	p.Pro249Leu	missense	Exon 7 of 7	ENSP00000431553.1	E9PKP1
	NPIPB5	ENST00000621622.5	TSL:1	c.*1257C>T		3_prime_UTR	Exon 4 of 4	ENSP00000481340.2	A0A087WXW0

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 2 AN: 17616 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0143

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: 0.000149

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000590 AC: 26 AN: 440862 Hom.: 0 Cov.: 0 AF XY: 0.0000560 AC XY: 13 AN XY: 232076

⚠️ 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: 12474

American (AMR) AF: 0.0000534 AC: 1 AN: 18710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13660

East Asian (EAS) AF: 0.00 AC: 0 AN: 30638

South Asian (SAS) AF: 0.00 AC: 0 AN: 45718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1938

European-Non Finnish (NFE) AF: 0.0000950 AC: 25 AN: 263242

Other (OTH) AF: 0.00 AC: 0 AN: 25598

⚠️ 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: 0.000114 AC: 2 AN: 17616 Hom.: 0 Cov.: 4 AF XY: 0.000243 AC XY: 2 AN XY: 8218

⚠️ 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: 6392

American (AMR) AF: 0.00 AC: 0 AN: 1646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 416

East Asian (EAS) AF: 0.00 AC: 0 AN: 468

South Asian (SAS) AF: 0.00 AC: 0 AN: 506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.000149 AC: 1 AN: 6696

Other (OTH) AF: 0.00 AC: 0 AN: 200

⚠️ 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.

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	0.20
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.79	T
PhyloP100		0.67
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.077
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.24
MVP		0.45
ClinPred		0.96	D
Varity_R		0.16
gMVP		0.011
Mutation Taster		=98/2	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: rs1325942907; hg19: chr16-22545050; COSMIC: COSV106114961; COSMIC: COSV106114961;