chr16-14951787-C-A

Position:

• chr16-14951787-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006985.4(NPIPA1):​c.815C>A​(p.Thr272Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000747 in 132,576 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T272S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (3 hom., cov: 23)
  • Exomes 𝑓: 0.0086 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPIPA1 NM_006985.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.46

Genes affected

NPIPA1 (HGNC:7909): (nuclear pore complex interacting protein family member A1) Predicted to be involved in mRNA transport and protein transport. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PKD1P3-NPIPA1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008986831).
• BP6: Variant 16-14951787-C-A is Benign according to our data. Variant chr16-14951787-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2343014.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPIPA1	NM_006985.4	c.815C>A	p.Thr272Asn	missense_variant	8/8	ENST00000328085.10
PKD1P3-NPIPA1	NR_146231.1	n.7092C>A		non_coding_transcript_exon_variant	39/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPIPA1	ENST00000328085.10	c.815C>A	p.Thr272Asn	missense_variant	8/8	1	NM_006985.4	P1
NPIPA1	ENST00000472413.5	n.5072C>A		non_coding_transcript_exon_variant	28/28	2
NPIPA1	ENST00000541836.5	n.2660C>A		non_coding_transcript_exon_variant	20/20	5

Frequencies

GnomAD3 genomes AF: 0.000732 AC: 97 AN: 132506 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.000633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00252

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000903

Gnomad SAS AF: 0.00114

Gnomad FIN AF: 0.000233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000532

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00114 AC: 235 AN: 206122 Hom.: 18 AF XY: 0.00108 AC XY: 122 AN XY: 112450

Gnomad AFR exome AF: 0.000977

Gnomad AMR exome AF: 0.00262

Gnomad ASJ exome AF: 0.000315

Gnomad EAS exome AF: 0.00233

Gnomad SAS exome AF: 0.00197

Gnomad FIN exome AF: 0.000275

Gnomad NFE exome AF: 0.000623

Gnomad OTH exome AF: 0.000186

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00858 AC: 11362 AN: 1323906 Hom.: 7 Cov.: 33 AF XY: 0.00862 AC XY: 5675 AN XY: 658562

Gnomad4 AFR exome AF: 0.00322

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.00355

Gnomad4 EAS exome AF: 0.0235

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.00881

Gnomad4 NFE exome AF: 0.00784

Gnomad4 OTH exome AF: 0.00723

GnomAD4 genome AF: 0.000747 AC: 99 AN: 132576 Hom.: 3 Cov.: 23 AF XY: 0.000608 AC XY: 39 AN XY: 64194

Gnomad4 AFR AF: 0.000657

Gnomad4 AMR AF: 0.00253

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000904

Gnomad4 SAS AF: 0.00143

Gnomad4 FIN AF: 0.000233

Gnomad4 NFE AF: 0.000532

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00315 Hom.: 10

ExAC AF: 0.000442 AC: 48

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2023

The c.815C>A (p.T272N) alteration is located in exon 8 (coding exon 8) of the NPIPA1 gene. This alteration results from a C to A substitution at nucleotide position 815, causing the threonine (T) at amino acid position 272 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

NPIPA1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.10
DANN	Benign	0.32
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.0030
Sift	Benign	0.31	T
Sift4G	Benign	0.31	T
Polyphen		0.15	B
Vest4		0.091
MVP		0.030
MPC		2.2
ClinPred		0.0047	T
Varity_R		0.10
gMVP		0.0054

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

Publications

LitVar

Other links and lift over

dbSNP: rs201684129; hg19: chr16-15045644; COSMIC: COSV60154185; COSMIC: COSV60154185;