rs1555904582

Variant summary

Our verdict is Uncertain significance. Variant got 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

5
8
4

Clinical Significance

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

Conservation

PhyloP100: 5.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
ANOS1NM_000216.4 linkc.158G>A p.Cys53Tyr missense_variant Exon 1 of 14 ENST00000262648.8 NP_000207.2 P23352
ANOS1XM_005274501.5 linkc.158G>A p.Cys53Tyr missense_variant Exon 1 of 9 XP_005274558.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANOS1ENST00000262648.8 linkc.158G>A p.Cys53Tyr missense_variant Exon 1 of 14 1 NM_000216.4 ENSP00000262648.3 P23352

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1079955
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
353505
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
25

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
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.85
T
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-5.4
D
REVEL
Uncertain
0.60
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.69
P
Vest4
0.74
MutPred
0.72
Loss of catalytic residue at L54 (P = 0.0151);
MVP
0.95
MPC
2.5
ClinPred
0.99
D
GERP RS
2.7
Varity_R
0.72
gMVP
0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555904582; hg19: chrX-8699920; API