Genetic Variant NANOS1:p.Ala173del (chr10-119030300-CCCG-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4_SupportingPP5BS2_Supporting

The NM_199461.4(NANOS1):c.517_519delGCC(p.Ala173del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,137,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 0 hom. )

Consequence

NANOS1
NM_199461.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

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 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_199461.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 10-119030300-CCCG-C is Pathogenic according to our data. Variant chr10-119030300-CCCG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 65391.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 40 Unknown,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199461.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANOS1	NM_199461.4	MANE Select	c.517_519delGCC	p.Ala173del	conservative_inframe_deletion	Exon 1 of 1	NP_955631.1	Q8WY41

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANOS1	ENST00000425699.3	TSL:6 MANE Select	c.517_519delGCC	p.Ala173del	conservative_inframe_deletion	Exon 1 of 1	ENSP00000393275.1	Q8WY41
	NANOS1	ENST00000340087.5	TSL:6	c.-125_-123delCCG		upstream_gene	N/A	ENSP00000345924.5	Q5T9H5

Frequencies

GnomAD3 genomes

AF:

0.000271

AC:

AN:

147534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000202

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000786

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000438

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00813

AC:

AN:

492

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.500

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00824

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00163

AC:

1614

AN:

989464

Hom.:

AF XY:

0.00183

AC XY:

856

AN XY:

466718

show subpopulations

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

African (AFR)

AF:

0.00167

AC:

AN:

19754

American (AMR)

AF:

0.00776

AC:

AN:

5796

Ashkenazi Jewish (ASJ)

AF:

0.00426

AC:

AN:

10796

East Asian (EAS)

AF:

0.00670

AC:

125

AN:

18644

South Asian (SAS)

AF:

0.000215

AC:

AN:

18608

European-Finnish (FIN)

AF:

0.00848

AC:

143

AN:

16860

Middle Eastern (MID)

AF:

0.00242

AC:

AN:

2476

European-Non Finnish (NFE)

AF:

0.00130

AC:

1115

AN:

859032

Other (OTH)

AF:

0.00259

AC:

AN:

37498

⚠️ 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

190

380

570

760

950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000271

AC:

AN:

147630

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

AN XY:

71952

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41024

American (AMR)

AF:

0.000201

AC:

AN:

14900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000786

AC:

AN:

8908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000438

AC:

AN:

66274

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000272

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spermatogenic failure 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=79/21

disease causing (ClinVar)

(source)

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

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10-119030300-CCCGCCGCCGCCG-CCCGCCGCCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over