14-50806738-T-A

Variant names:

• chr14-50806738-T-A
• rs61755037
• NM_020921.4:c.264A>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_020921.4(NIN):​c.264A>T​(p.Pro88Pro) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00146 in 1,557,114 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P88P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (27 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (15 hom.)
• Consequence: NIN NM_020921.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.70
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16).
• BP6: Variant 14-50806738-T-A is Benign according to our data. Variant chr14-50806738-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00795 (1211/152318) while in subpopulation AFR AF = 0.0283 (1176/41574). AF 95% confidence interval is 0.0269. There are 27 homozygotes in GnomAd4. There are 573 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.264A>T	p.Pro88Pro	splice_region synonymous	Exon 4 of 31	NP_065972.4
	NIN	NM_182946.2		c.264A>T	p.Pro88Pro	splice_region synonymous	Exon 4 of 30	NP_891991.2
	NIN	NM_182944.3		c.264A>T	p.Pro88Pro	splice_region synonymous	Exon 4 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.264A>T	p.Pro88Pro	splice_region synonymous	Exon 4 of 31	ENSP00000436092.2
	NIN	ENST00000382041.7	TSL:1	c.264A>T	p.Pro88Pro	splice_region synonymous	Exon 4 of 30	ENSP00000371472.3
	NIN	ENST00000382043.8	TSL:1	c.264A>T	p.Pro88Pro	splice_region synonymous	Exon 3 of 28	ENSP00000371474.4

Frequencies

GnomAD3 genomes AF: 0.00793 AC: 1207 AN: 152200 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00193 AC: 474 AN: 245524 AF XY: 0.00134

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.000885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000679

GnomAD4 exome AF: 0.000757 AC: 1064 AN: 1404796 Hom.: 15 Cov.: 23 AF XY: 0.000648 AC XY: 455 AN XY: 702162

African (AFR) AF: 0.0284 AC: 909 AN: 31954

American (AMR) AF: 0.000940 AC: 41 AN: 43630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 39076

South Asian (SAS) AF: 0.0000357 AC: 3 AN: 83992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5650

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1063042

Other (OTH) AF: 0.00169 AC: 99 AN: 58460

GnomAD4 genome AF: 0.00795 AC: 1211 AN: 152318 Hom.: 27 Cov.: 33 AF XY: 0.00769 AC XY: 573 AN XY: 74472

African (AFR) AF: 0.0283 AC: 1176 AN: 41574

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00236 Hom.: 1

Bravo AF: 0.00901

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	NIN-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		4.7
PromoterAI		-0.073	Neutral
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.050		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: rs61755037; hg19: chr14-51273456;