Genetic Variant NANOS1:p.Ala170_Ala173dup (chr10-119030300-C-CCCGCCGCCGCCG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_199461.4(NANOS1):c.508_519dupGCCGCCGCCGCC(p.Ala170_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 0.00000678 in 147,538 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: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 9.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NANOS1
NM_199461.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

Publications

1 publications found

Variant links:

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)

NANOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.508_519dupGCCGCCGCCGCC	p.Ala170_Ala173dup	conservative_inframe_insertion	Exon 1 of 1	ENST00000425699.3	NP_955631.1	Q8WY41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NANOS1	ENST00000425699.3 link	c.508_519dupGCCGCCGCCGCC	p.Ala170_Ala173dup	conservative_inframe_insertion	Exon 1 of 1	6	NM_199461.4	ENSP00000393275.1		Q8WY41
NANOS1	ENST00000340087.5 link	c.-126_-125insCCGCCGCCGCCG		upstream_gene_variant		6		ENSP00000345924.5		Q5T9H5

Frequencies

GnomAD3 genomes

AF:

0.00000678

AC:

AN:

147538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.93e-7

AC:

AN:

1006558

Hom.:

Cov.:

AF XY:

0.00000211

AC XY:

AN XY:

474868

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000499

AC:

AN:

20058

American (AMR)

AF:

0.00

AC:

AN:

5958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11002

East Asian (EAS)

AF:

0.00

AC:

AN:

18964

South Asian (SAS)

AF:

0.00

AC:

AN:

18904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2528

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

873626

Other (OTH)

AF:

0.00

AC:

AN:

38176

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000678

AC:

AN:

147538

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71850

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

40912

American (AMR)

AF:

0.00

AC:

AN:

14884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

5088

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66284

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=81/19

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over