10-119030030-CCCT-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_199461.4(NANOS1):c.240_242del(p.Ser83del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.006 in 1,385,068 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (35 hom.)
• Consequence: NANOS1 NM_199461.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 2.57

Genes affected

NANOS1 (HGNC:23044): (nanos C2HC-type zinc finger 1) This gene encodes a CCHC-type zinc finger protein that is a member of the nanos family. This protein co-localizes with the RNA-binding protein pumilio RNA-binding family member 2 and may be involved in regulating translation as a post-transcriptional repressor. Mutations in this gene are associated with spermatogenic impairment. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 10-119030030-CCCT-C is Benign according to our data. Variant chr10-119030030-CCCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 65390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 865 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NANOS1	NM_199461.4	c.240_242del	p.Ser83del	inframe_deletion	1/1	ENST00000425699.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NANOS1	ENST00000425699.3	c.240_242del	p.Ser83del	inframe_deletion	1/1		NM_199461.4	P1

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 865 AN: 149962 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.00526

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00642

Gnomad OTH AF: 0.00194

GnomAD3 exomes AF: 0.00376 AC: 147 AN: 39138 Hom.: 1 AF XY: 0.00391 AC XY: 88 AN XY: 22508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000967

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.000745

Gnomad SAS exome AF: 0.00100

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.00526

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00603 AC: 7446 AN: 1234998 Hom.: 35 AF XY: 0.00584 AC XY: 3529 AN XY: 604126

Gnomad4 AFR exome AF: 0.000671

Gnomad4 AMR exome AF: 0.000683

Gnomad4 ASJ exome AF: 0.00382

Gnomad4 EAS exome AF: 0.0000369

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.00623

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.00576 AC: 865 AN: 150070 Hom.: 1 Cov.: 32 AF XY: 0.00698 AC XY: 511 AN XY: 73236

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00526

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0337

Gnomad4 NFE AF: 0.00642

Gnomad4 OTH AF: 0.00192

Bravo AF: 0.00311

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 12 Pathogenic:1 Benign:1

Likely benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_199461.2:c.240_242delCTC in the NANOS1 gene has an allele frequency of 0.022 in European (Finnish) subpopulation in the gnomAD database. This in-frame deletion happens in a repetitive region without known function. Kusz-Zamelczyk et al. reported this variant as p.Pro77_Ser78delinsPro (PMID: 23315541). Using the quantitative yeast two-hybrid assay, the author tested both mutated NANOS1 alleles for interaction with GEMIN3, and found that the p.Pro34Thr, p.Pro77_Ser78delinsPro allele reduced interaction with GEMIN3 by 14% (PMID: 23315541). In one pedigree, the variant segregate with the phenotype. In contrary, in the second pedigree (patient 2), the father passed this variant to his son, indicating his father is fertile although he has this variant. Taken together, we interprete this variant as Benign/Likely benign variant (PMID: 23315541). ACMG/AMP criteria applied: BS1, BP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NANOS1: PM4:Supporting, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	- -

NANOS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2021

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

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: rs587777031; hg19: chr10-120789542;