16-22534043-G-A

Variant names:

• chr16-22534043-G-A
• rs550992191
• NM_001395849.1:c.1060G>A

Variant summary

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

The NM_001395849.1(NPIPB5):​c.1060G>A​(p.Ala354Thr) 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. A354S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPB5 NM_001395849.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.15
• 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=0.040662378).

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.1060G>A	p.Ala354Thr	missense	Exon 7 of 7	NP_001382778.1	A8MRT5
	NPIPB5	NM_001135865.3		c.1060G>A	p.Ala354Thr	missense	Exon 9 of 9	NP_001129337.1	A8MRT5
	NPIPB5	NM_001395850.1		c.1060G>A	p.Ala354Thr	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.1060G>A	p.Ala354Thr	missense	Exon 7 of 7	ENSP00000440703.1	A8MRT5
	NPIPB5	ENST00000528249.5	TSL:1	c.1060G>A	p.Ala354Thr	missense	Exon 7 of 7	ENSP00000431553.1	E9PKP1
	NPIPB5	ENST00000517539.6	TSL:5	c.1060G>A	p.Ala354Thr	missense	Exon 8 of 8	ENSP00000430633.1	A8MRT5

Frequencies

GnomAD3 genomes AF: 0.000123 AC: 15 AN: 121958 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.000422

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000804 AC: 5 AN: 62182 AF XY: 0.0000646

Gnomad AFR exome AF: 0.000511

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: 0.0000787

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000119 AC: 17 AN: 1425994 Hom.: 0 Cov.: 33 AF XY: 0.0000127 AC XY: 9 AN XY: 710406

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

African (AFR) AF: 0.000210 AC: 7 AN: 33314

American (AMR) AF: 0.0000226 AC: 1 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39138

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41006

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4118

European-Non Finnish (NFE) AF: 0.00000641 AC: 7 AN: 1092708

Other (OTH) AF: 0.00 AC: 0 AN: 59528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000737202), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000123 AC: 15 AN: 122078 Hom.: 0 Cov.: 15 AF XY: 0.000136 AC XY: 8 AN XY: 59006

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

African (AFR) AF: 0.000421 AC: 15 AN: 35634

American (AMR) AF: 0.00 AC: 0 AN: 11682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3048

East Asian (EAS) AF: 0.00 AC: 0 AN: 3418

South Asian (SAS) AF: 0.00 AC: 0 AN: 3636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54308

Other (OTH) AF: 0.00 AC: 0 AN: 1684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000636808), 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	0.22
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.2
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.066
Sift	Benign	0.33	T
Sift4G	Benign	0.26	T
Polyphen		0.93	P
Vest4		0.070
MutPred		0.30		Gain of glycosylation at A354 (P = 0.0065)
MVP		0.030
ClinPred		0.027	T
Varity_R		0.067
gMVP		0.0047

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: rs550992191; hg19: chr16-22545364;