dbSNP rs1555904582: ANOS1:p.Cys53Tyr (chrX-8731879-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000216.4(ANOS1):c.158G>A(p.Cys53Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C53R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

ANOS1
NM_000216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.91

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANOS1	NM_000216.4 link	c.158G>A	p.Cys53Tyr	missense_variant	Exon 1 of 14	ENST00000262648.8	NP_000207.2
ANOS1	NM_001440775.1 link	c.158G>A	p.Cys53Tyr	missense_variant	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.158G>A	p.Cys53Tyr	missense_variant	Exon 1 of 14	1	NM_000216.4	ENSP00000262648.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1079955

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

353505

African (AFR)

AF:

0.00

AC:

AN:

24381

American (AMR)

AF:

0.00

AC:

AN:

34110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18818

East Asian (EAS)

AF:

0.00

AC:

AN:

28560

South Asian (SAS)

AF:

0.00

AC:

AN:

52283

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38813

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2848

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

834969

Other (OTH)

AF:

0.00

AC:

AN:

45173

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia

Uncertain:2

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) (MIM#308700). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Cys-box domain and disrupts a disulphide bond (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by a clinical laboratory in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ANOS1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 53 of the ANOS1 protein (p.Cys53Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.4

PhyloP100

5.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.60

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0020

Polyphen

0.69

Vest4

0.74

MutPred

0.72

Loss of catalytic residue at L54 (P = 0.0151);

MVP

0.95

MPC

2.5

ClinPred

0.99

GERP RS

2.7

PromoterAI

-0.074

Neutral

(source)

Varity_R

0.72

gMVP

0.98

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: 3

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over