Genetic Variant NIN:p.Ala1755Glu (chr14-50743453-G-T) – 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_020921.4(NIN):c.5264C>A(p.Ala1755Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A1755T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NIN
NM_020921.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.06

Publications

0 publications found

Variant links:

Genes affected

NIN (HGNC:14906): (ninein) This gene encodes one of the proteins important for centrosomal function. This protein is important for positioning and anchoring the microtubules minus-ends in epithelial cells. Localization of this protein to the centrosome requires three leucine zippers in the central coiled-coil domain. Multiple alternatively spliced transcript variants that encode different isoforms have been reported. [provided by RefSeq, Jul 2008]

NIN Gene-Disease associations (from GenCC):

Seckel syndrome 7
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

NIN links:

LOC124903313 (HGNC:):

LOC124903313 links:

Genome browser will be placed here

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=0.034130424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIN	NM_020921.4 link	c.5264C>A	p.Ala1755Glu	missense_variant	Exon 24 of 31	ENST00000530997.7	NP_065972.4	Q8N4C6-7Q5XUU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIN	ENST00000530997.7 link	c.5264C>A	p.Ala1755Glu	missense_variant	Exon 24 of 31	5	NM_020921.4	ENSP00000436092.2		Q8N4C6-7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461116

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726908

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111338

Other (OTH)

AF:

0.00

AC:

AN:

60366

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.013

.;.;.;.;T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.82

T;.;.;T;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.034

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.4

N;N;.;.;N;.

PhyloP100

4.1

PrimateAI

Benign

0.23

PROVEAN

Benign

1.6

N;.;N;.;N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;.;T;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;B;B

Vest4

0.14

MutPred

0.22

Gain of ubiquitination at K1758 (P = 0.0447);Gain of ubiquitination at K1758 (P = 0.0447);.;.;Gain of ubiquitination at K1758 (P = 0.0447);Gain of ubiquitination at K1758 (P = 0.0447);

MVP

0.54

MPC

0.14

ClinPred

0.18

GERP RS

4.2

Varity_R

0.072

gMVP

0.020

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over