rs192017781

chr14-50757383-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020921.4(NIN):c.3647G>A(p.Arg1216Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: NIN NM_020921.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.386

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024294227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIN	NM_020921.4	c.3647G>A	p.Arg1216Gln	missense_variant	18/31	ENST00000530997.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIN	ENST00000530997.7	c.3647G>A	p.Arg1216Gln	missense_variant	18/31	5	NM_020921.4	P2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.000353

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000334 AC: 84 AN: 251128 Hom.: 0 AF XY: 0.000354 AC XY: 48 AN XY: 135746

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000510 AC: 745 AN: 1461740 Hom.: 0 Cov.: 64 AF XY: 0.000484 AC XY: 352 AN XY: 727166

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000601

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152276 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74452

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000503 Hom.: 1

Bravo AF: 0.000382

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2022	The c.3647G>A (p.R1216Q) alteration is located in exon 18 (coding exon 16) of the NIN gene. This alteration results from a G to A substitution at nucleotide position 3647, causing the arginine (R) at amino acid position 1216 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2015	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1216 of the NIN protein (p.Arg1216Gln). This variant is present in population databases (rs192017781, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NIN-related conditions. ClinVar contains an entry for this variant (Variation ID: 211610). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.035
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.47	N;.;N;N
REVEL	Benign	0.058
Sift	Benign	0.17	T;.;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.34	B;B;B;B
Vest4		0.11
MVP		0.32
MPC		0.33
ClinPred		0.018	T
GERP RS		4.9
Varity_R		0.068
gMVP		0.074

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: rs192017781; hg19: chr14-51224101; COSMIC: COSV55402482;