X-8532999-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000216.4(ANOS1):ā€‹c.2039A>Gā€‹(p.Tyr680Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000962 in 1,039,870 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 23)
Exomes š‘“: 9.6e-7 ( 0 hom. 0 hem. )

Consequence

ANOS1
NM_000216.4 missense

Scores

7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.05
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12939015).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANOS1NM_000216.4 linkuse as main transcriptc.2039A>G p.Tyr680Cys missense_variant 14/14 ENST00000262648.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANOS1ENST00000262648.8 linkuse as main transcriptc.2039A>G p.Tyr680Cys missense_variant 14/141 NM_000216.4 P1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.62e-7
AC:
1
AN:
1039870
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
320332
show subpopulations
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:
0.0000190
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 08, 2020This sequence change replaces tyrosine with cysteine at codon 680 of the ANOS1 protein (p.Tyr680Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ANOS1-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.17
T
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.82
T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.19
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.011
D
Polyphen
0.011
B
Vest4
0.48
MutPred
0.25
Loss of phosphorylation at Y680 (P = 0.013);
MVP
0.27
MPC
0.59
ClinPred
0.78
D
GERP RS
1.3
Varity_R
0.20
gMVP
0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-8501040; API