X-8732036-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000216.4(ANOS1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000116 in 862,259 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000012 ( 0 hom. 0 hem. )

Consequence

ANOS1
NM_000216.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.47

Publications

1 publications found

Variant links:

Genes affected

ANOS1 (HGNC:6211): (anosmin 1) Mutations in this gene cause the X-linked Kallmann syndrome. The encoded protein is similar in sequence to proteins known to function in neural cell adhesion and axonal migration. In addition, this cell surface protein is N-glycosylated and may have anti-protease activity. [provided by RefSeq, Jul 2008]

ANOS1 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 1 with or without anosmia
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ANOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 45 pathogenic variants. Next in-frame start position is after 335 codons. Genomic position: 8570558. Lost 0.491 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-8732036-T-C is Pathogenic according to our data. Variant chrX-8732036-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 140614.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANOS1	NM_000216.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENST00000262648.8	NP_000207.2
ANOS1	NM_001440775.1 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9		NP_001427704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	1	NM_000216.4	ENSP00000262648.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000116

AC:

AN:

862259

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

262115

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17624

American (AMR)

AF:

0.00

AC:

AN:

6267

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10594

East Asian (EAS)

AF:

0.00

AC:

AN:

19065

South Asian (SAS)

AF:

0.00

AC:

AN:

20173

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2073

European-Non Finnish (NFE)

AF:

0.00000138

AC:

AN:

724897

Other (OTH)

AF:

0.00

AC:

AN:

34824

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

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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia

Pathogenic:1

May 01, 2013

Endocrinology Clinic, Seth G.S. Medical College

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

ANOS1-related disorder

Pathogenic:1

Sep 29, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ANOS1 c.1A>G variant is predicted to disrupt the translation initiation site (p.Met1?). This variant was previously reported in the hemizygous state in individuals with congenital hypogonadotropic hypogonadism/Kallmann syndrome (see, for example, Nair et al. 2016. PubMed ID: 26708526, figure 1, family 2; Amato et al. 2019. PubMed ID: 31200363). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.12

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

-0.13

PhyloP100

3.5

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.71

Vest4

0.89

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.1474);

MVP

0.99

ClinPred

0.54

GERP RS

3.0

PromoterAI

-0.35

Neutral

(source)

Varity_R

0.92

gMVP

0.70

Mutation Taster

=19/181

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over