NM_001395849.1:c.1036C>G

Variant names:

• chr16-22534019-C-G
• rs563656604
• NM_001395849.1:c.1036C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001395849.1(NPIPB5):​c.1036C>G​(p.Leu346Val) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPB5 NM_001395849.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.206
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022234142).

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.1036C>G	p.Leu346Val	missense	Exon 7 of 7	NP_001382778.1	A8MRT5
	NPIPB5	NM_001135865.3		c.1036C>G	p.Leu346Val	missense	Exon 9 of 9	NP_001129337.1	A8MRT5
	NPIPB5	NM_001395850.1		c.1036C>G	p.Leu346Val	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.1036C>G	p.Leu346Val	missense	Exon 7 of 7	ENSP00000440703.1	A8MRT5
	NPIPB5	ENST00000528249.5	TSL:1	c.1036C>G	p.Leu346Val	missense	Exon 7 of 7	ENSP00000431553.1	E9PKP1
	NPIPB5	ENST00000517539.6	TSL:5	c.1036C>G	p.Leu346Val	missense	Exon 8 of 8	ENSP00000430633.1	A8MRT5

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 59 AN: 116402 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.000320

Gnomad AMI AF: 0.00163

Gnomad AMR AF: 0.000352

Gnomad ASJ AF: 0.000699

Gnomad EAS AF: 0.000304

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000620

GnomAD2 exomes AF: 0.0000645 AC: 4 AN: 62054 AF XY: 0.0000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000397 AC: 56 AN: 1410562 Hom.: 0 Cov.: 33 AF XY: 0.0000398 AC XY: 28 AN XY: 703338

⚠️ 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: 33238

American (AMR) AF: 0.0000681 AC: 3 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 85712

European-Finnish (FIN) AF: 0.0000731 AC: 3 AN: 41034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.0000417 AC: 45 AN: 1078034

Other (OTH) AF: 0.0000169 AC: 1 AN: 59028

⚠️ 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: 0.000515 AC: 60 AN: 116510 Hom.: 0 Cov.: 15 AF XY: 0.000530 AC XY: 30 AN XY: 56588

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

African (AFR) AF: 0.000320 AC: 11 AN: 34426

American (AMR) AF: 0.000351 AC: 4 AN: 11392

Ashkenazi Jewish (ASJ) AF: 0.000699 AC: 2 AN: 2862

East Asian (EAS) AF: 0.000304 AC: 1 AN: 3290

South Asian (SAS) AF: 0.000289 AC: 1 AN: 3464

European-Finnish (FIN) AF: 0.00111 AC: 8 AN: 7232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.000603 AC: 31 AN: 51388

Other (OTH) AF: 0.000613 AC: 1 AN: 1632

⚠️ 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: 0.000797 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	0.27
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.7
DANN	Benign	0.40
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.21
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.081
Sift	Benign	0.24	T
Sift4G	Benign	0.24	T
Polyphen		0.33	B
Vest4		0.065
MutPred		0.39		Loss of catalytic residue at L346 (P = 0.0226)
MVP		0.014
ClinPred		0.046	T
Varity_R		0.099
gMVP		0.0023
Mutation Taster		=93/7	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: rs563656604; hg19: chr16-22545340; COSMIC: COSV69995145; COSMIC: COSV69995145;