rs41313507

Positions:

• chr14-50758043-G-A
• chr14-50758043-G-C

Variant summary

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

The NM_020921.4(NIN):​c.2987C>T​(p.Ala996Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,614,162 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. A996G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (17 hom.)
• Consequence: NIN NM_020921.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0110

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023878217).
• BP6: Variant 14-50758043-G-A is Benign according to our data. Variant chr14-50758043-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211604.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr14-50758043-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIN	NM_020921.4	c.2987C>T	p.Ala996Val	missense_variant	18/31	ENST00000530997.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIN	ENST00000530997.7	c.2987C>T	p.Ala996Val	missense_variant	18/31	5	NM_020921.4	P2

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00224 AC: 563 AN: 251448 Hom.: 0 AF XY: 0.00227 AC XY: 308 AN XY: 135904

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00389

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00396 AC: 5795 AN: 1461886 Hom.: 17 Cov.: 42 AF XY: 0.00388 AC XY: 2820 AN XY: 727246

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.00219 AC XY: 163 AN XY: 74440

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00391

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00339 Hom.: 1

Bravo AF: 0.00251

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00215 AC: 261

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 16, 2020

- -

NIN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2022

This variant is classified as likely 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	0.072
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.070
DANN	Benign	0.70
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.28	N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.55	N;.;N;N
REVEL	Benign	0.045
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.015	B;B;B;B
Vest4		0.032
MVP		0.14
MPC		0.12
ClinPred		0.0040	T
GERP RS		-11
Varity_R		0.017
gMVP		0.016

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: rs41313507; hg19: chr14-51224761; COSMIC: COSV99813222;