chrX-8534420-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000216.4(ANOS1):​c.1883C>T​(p.Thr628Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,954 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

ANOS1
NM_000216.4 missense

Scores

1
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANOS1NM_000216.4 linkuse as main transcriptc.1883C>T p.Thr628Ile missense_variant 13/14 ENST00000262648.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANOS1ENST00000262648.8 linkuse as main transcriptc.1883C>T p.Thr628Ile missense_variant 13/141 NM_000216.4 P1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1096954
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
362322
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000238
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 22, 2017The T628I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T628I is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.090
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.24
T
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.85
T
M_CAP
Pathogenic
0.82
D
MetaRNN
Uncertain
0.50
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.51
N
MutationTaster
Benign
0.98
N
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.23
Sift
Benign
0.046
D
Sift4G
Uncertain
0.020
D
Polyphen
0.27
B
Vest4
0.32
MutPred
0.75
Loss of disorder (P = 0.0927);
MVP
0.34
MPC
0.33
ClinPred
0.75
D
GERP RS
4.2
Varity_R
0.11
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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: rs1064796699; hg19: chrX-8502461; API