14-50757543-C-G

Variant names:

• chr14-50757543-C-G
• rs139059875
• NM_020921.4:c.3487G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020921.4(NIN):​c.3487G>C​(p.Val1163Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,116 control chromosomes in the GnomAD database, including 5 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: NIN NM_020921.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.08
• Publications: 4 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: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047183335).
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIN	NM_020921.4	MANE Select	c.3487G>C	p.Val1163Leu	missense	Exon 18 of 31	NP_065972.4
	NIN	NM_182946.2		c.3487G>C	p.Val1163Leu	missense	Exon 18 of 30	NP_891991.2
	NIN	NM_182944.3		c.3487G>C	p.Val1163Leu	missense	Exon 18 of 30	NP_891989.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIN	ENST00000530997.7	TSL:5 MANE Select	c.3487G>C	p.Val1163Leu	missense	Exon 18 of 31	ENSP00000436092.2
	NIN	ENST00000382041.7	TSL:1	c.3487G>C	p.Val1163Leu	missense	Exon 18 of 30	ENSP00000371472.3
	NIN	ENST00000382043.8	TSL:1	c.2399+2314G>C		intron	N/A	ENSP00000371474.4

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152148 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00157

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000728 AC: 183 AN: 251374 AF XY: 0.000832

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00155 AC: 2265 AN: 1461850 Hom.: 4 Cov.: 64 AF XY: 0.00147 AC XY: 1072 AN XY: 727226

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00193 AC: 2151 AN: 1111996

Other (OTH) AF: 0.00124 AC: 75 AN: 60394

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152266 Hom.: 1 Cov.: 31 AF XY: 0.000685 AC XY: 51 AN XY: 74478

African (AFR) AF: 0.000385 AC: 16 AN: 41536

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68030

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000858

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.000684 AC: 83

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.36
DANN	Benign	0.19
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.76	N
PhyloP100		-1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.026
Sift	Benign	0.36	T
Sift4G	Benign	0.89	T
Polyphen		0.0010	B
Vest4		0.062
MVP		0.20
MPC		0.12
ClinPred		0.0088	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.086
Mutation Taster		=98/2	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: rs139059875; hg19: chr14-51224261; COSMIC: COSV99815930;