rs41299193

Variant names:

• chr14-50756742-T-A
• rs41299193
• NM_020921.4:c.4288A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020921.4(NIN):​c.4288A>T​(p.Ile1430Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,551,684 control chromosomes in the GnomAD database, including 6 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1430T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (6 hom.)
• Consequence: NIN NM_020921.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.490
• Publications: 5 publications found

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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004059702).
• BP6: Variant 14-50756742-T-A is Benign according to our data. Variant chr14-50756742-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 211613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020921.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIN	NM_020921.4	MANE Select	c.4288A>T	p.Ile1430Leu	missense	Exon 18 of 31	NP_065972.4
	NIN	NM_182946.2		c.4288A>T	p.Ile1430Leu	missense	Exon 18 of 30	NP_891991.2	Q8N4C6-1
	NIN	NM_182944.3		c.4288A>T	p.Ile1430Leu	missense	Exon 18 of 30	NP_891989.3	C9J066

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIN	ENST00000530997.7	TSL:5 MANE Select	c.4288A>T	p.Ile1430Leu	missense	Exon 18 of 31	ENSP00000436092.2	Q8N4C6-7
	NIN	ENST00000382041.7	TSL:1	c.4288A>T	p.Ile1430Leu	missense	Exon 18 of 30	ENSP00000371472.3	Q8N4C6-1
	NIN	ENST00000382043.8	TSL:1	c.2400-1875A>T		intron	N/A	ENSP00000371474.4	Q8N4C6-11

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00196 AC: 303 AN: 154624 AF XY: 0.00218

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.000403

Gnomad ASJ exome AF: 0.000468

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000784

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.00351 AC: 4917 AN: 1399326 Hom.: 6 Cov.: 30 AF XY: 0.00356 AC XY: 2456 AN XY: 690178

African (AFR) AF: 0.000696 AC: 22 AN: 31598

American (AMR) AF: 0.000560 AC: 20 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 15 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00218 AC: 173 AN: 79244

European-Finnish (FIN) AF: 0.00114 AC: 56 AN: 49188

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.00410 AC: 4425 AN: 1078974

Other (OTH) AF: 0.00353 AC: 205 AN: 58000

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74504

African (AFR) AF: 0.000890 AC: 37 AN: 41584

American (AMR) AF: 0.000849 AC: 13 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00365 AC: 248 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00344 Hom.: 1

Bravo AF: 0.00198

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00268 AC: 19

ExAC AF: 0.00152 AC: 67

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	NIN-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0020
DANN	Benign	0.21
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N
PhyloP100		-0.49
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.037
Sift	Benign	0.76	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.22		Gain of catalytic residue at E1433 (P = 0.0669)
MVP		0.081
MPC		0.12
ClinPred		0.0018	T
GERP RS		-11
Varity_R		0.024
gMVP		0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41299193; hg19: chr14-51223460;