10-119030300-CCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCGCCGCCGCCG

Variant names:

• chr10-119030300-C-CCCGCCGCCGCCGCCG
• rs538539239
• NM_199461.4:c.505_519dupGCCGCCGCCGCCGCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_199461.4(NANOS1):​c.505_519dupGCCGCCGCCGCCGCC​(p.Ala169_Ala173dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000993 in 1,006,558 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: NANOS1 NM_199461.4 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 0 publications found

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]

NANOS1 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 12

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_199461.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NANOS1	NM_199461.4	c.505_519dupGCCGCCGCCGCCGCC	p.Ala169_Ala173dup	conservative_inframe_insertion	Exon 1 of 1	ENST00000425699.3	NP_955631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NANOS1	ENST00000425699.3	c.505_519dupGCCGCCGCCGCCGCC	p.Ala169_Ala173dup	conservative_inframe_insertion	Exon 1 of 1	6	NM_199461.4	ENSP00000393275.1
NANOS1	ENST00000340087.5	c.-126_-125insCCGCCGCCGCCGCCG		upstream_gene_variant		6		ENSP00000345924.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.93e-7 AC: 1 AN: 1006558 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 474868

African (AFR) AF: 0.00 AC: 0 AN: 20058

American (AMR) AF: 0.00 AC: 0 AN: 5958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11002

East Asian (EAS) AF: 0.00 AC: 0 AN: 18964

South Asian (SAS) AF: 0.00 AC: 0 AN: 18904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2528

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 873626

Other (OTH) AF: 0.00 AC: 0 AN: 38176

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs538539239; hg19: chr10-120789812;