14-50729605-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020921.4(NIN):c.5996G>A(p.Arg1999His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,613,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. R1999C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 2 hom. )

Consequence

NIN
NM_020921.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.43

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004661709).

BP6

Variant 14-50729605-C-T is Benign according to our data. Variant chr14-50729605-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435996.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIN	NM_020921.4 link	c.5996G>A	p.Arg1999His	missense_variant	Exon 29 of 31	ENST00000530997.7	NP_065972.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIN	ENST00000530997.7 link	c.5996G>A	p.Arg1999His	missense_variant	Exon 29 of 31	5	NM_020921.4	ENSP00000436092.2

Frequencies

GnomAD3 genomes

AF:

0.000946

AC:

144

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00134

AC:

336

AN:

250846

AF XY:

0.00137

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000958

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.000980

AC:

1433

AN:

1461682

Hom.:

Cov.:

AF XY:

0.000939

AC XY:

683

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.00112

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0129

AC:

336

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.000220

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000805

AC:

895

AN:

1111934

Other (OTH)

AF:

0.00151

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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

AF:

0.000965

AC:

147

AN:

152280

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41558

American (AMR)

AF:

0.000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68024

Other (OTH)

AF:

0.000946

AC:

AN:

2114

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

Genome 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

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000945

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00125

AC:

152

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NIN: BP4, BS1, BS2

not specified

Uncertain:1

Nov 29, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NIN-related disorder

Benign:1

Jun 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.0

.;.;.;.;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.62

T;.;.;T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.0047

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.90

N;N;.;.;N;.

PhyloP100

1.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.22

N;.;N;.;N;N

REVEL

Benign

0.035

Sift

Benign

0.69

T;.;T;.;T;T

Sift4G

Benign

0.25

T;T;T;T;T;T

Vest4

0.098

ClinPred

0.019

GERP RS

2.9

Varity_R

0.019

gMVP

0.048

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over