Genetic Variant NDFIP2:p.Thr102Pro (chr13-79481507-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019080.3(NDFIP2):c.304A>C(p.Thr102Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,552,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

NDFIP2
NM_019080.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40

Variant links:

Genes affected

NDFIP2 (HGNC:18537): (Nedd4 family interacting protein 2) Enables WW domain binding activity. Involved in negative regulation of gene expression; negative regulation of transport; and positive regulation of protein ubiquitination. Located in several cellular components, including Golgi apparatus; mitochondrion; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NDFIP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15788406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDFIP2	NM_019080.3 link	c.304A>C	p.Thr102Pro	missense_variant	Exon 1 of 8	ENST00000218652.12	NP_061953.2	Q9NV92
NDFIP2	NM_001394685.1 link	c.304A>C	p.Thr102Pro	missense_variant	Exon 1 of 8		NP_001381614.1
NDFIP2	NM_001161407.2 link	c.304A>C	p.Thr102Pro	missense_variant	Exon 1 of 8		NP_001154879.1	B4DGY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDFIP2	ENST00000218652.12 link	c.304A>C	p.Thr102Pro	missense_variant	Exon 1 of 8	1	NM_019080.3	ENSP00000218652.7		Q9NV92

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000485

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000152

AC:

AN:

151084

Hom.:

AF XY:

0.000136

AC XY:

AN XY:

80632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000407

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000311

AC:

436

AN:

1400162

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

224

AN XY:

690860

show subpopulations

Gnomad4 AFR exome

AF:

0.0000635

Gnomad4 AMR exome

AF:

0.0000557

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000394

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.000256

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.0000758

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304A>C (p.T102P) alteration is located in exon 1 (coding exon 1) of the NDFIP2 gene. This alteration results from a A to C substitution at nucleotide position 304, causing the threonine (T) at amino acid position 102 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

T;T;T;T

Eigen

Benign

0.066

Eigen_PC

Benign

0.036

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.60

T;.;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.85

.;N;.;.

REVEL

Benign

0.15

Sift

Uncertain

0.0040

.;D;.;.

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.97

D;D;P;.

Vest4

0.44

MVP

0.76

MPC

2.1

ClinPred

0.15

GERP RS

1.8

Varity_R

0.25

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over