Genetic Variant NDFIP2:p.Gly29Arg (chr13-79481288-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019080.3(NDFIP2):c.85G>A(p.Gly29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000649 in 1,386,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G29E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

NDFIP2
NM_019080.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.406

Publications

1 publications found

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:

NDFIP2-AS1 (HGNC:40844): (NDFIP2 antisense RNA 1)

NDFIP2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040825397).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDFIP2	NM_019080.3	MANE Select	c.85G>A	p.Gly29Arg	missense	Exon 1 of 8	NP_061953.2	Q9NV92
NDFIP2	NM_001394685.1		c.85G>A	p.Gly29Arg	missense	Exon 1 of 8	NP_001381614.1
NDFIP2	NM_001161407.2		c.85G>A	p.Gly29Arg	missense	Exon 1 of 8	NP_001154879.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDFIP2	ENST00000218652.12	TSL:1 MANE Select	c.85G>A	p.Gly29Arg	missense	Exon 1 of 8	ENSP00000218652.7	Q9NV92
NDFIP2	ENST00000703122.1		c.-198G>A		5_prime_UTR	Exon 1 of 8	ENSP00000515183.1	A0A8V8TQM3
NDFIP2	ENST00000703126.1		c.-198G>A		5_prime_UTR	Exon 1 of 8	ENSP00000515186.1	A0A8V8TQN2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000751

AC:

AN:

133068

AF XY:

0.0000138

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000649

AC:

AN:

1386988

Hom.:

Cov.:

AF XY:

0.00000731

AC XY:

AN XY:

684346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31528

American (AMR)

AF:

0.00

AC:

AN:

35658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00000835

AC:

AN:

1078254

Other (OTH)

AF:

0.00

AC:

AN:

57836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.7

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0024

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.48

M_CAP

Benign

0.0049

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

PhyloP100

-0.41

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.39

REVEL

Benign

0.025

Sift

Benign

0.97

Sift4G

Benign

0.87

Polyphen

0.0010

Vest4

0.11

MutPred

0.19

Loss of loop (P = 0.0112)

MVP

0.13

MPC

1.3

ClinPred

0.025

GERP RS

0.069

PromoterAI

-0.086

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.027

gMVP

0.082

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over