chrX-8534432-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000216.4(ANOS1):​c.1871T>G​(p.Leu624Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

Frequency

Genomes: not found (cov: 22)

Consequence

ANOS1
NM_000216.4 missense

Scores

8
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANOS1NM_000216.4 linkuse as main transcriptc.1871T>G p.Leu624Arg missense_variant 13/14 ENST00000262648.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANOS1ENST00000262648.8 linkuse as main transcriptc.1871T>G p.Leu624Arg missense_variant 13/141 NM_000216.4 P1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
22

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 testingInvitaeFeb 27, 2020In 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: "Deleterious"; PolyPhen-2: "Benign"; 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). This sequence change replaces leucine with arginine at codon 624 of the ANOS1 protein (p.Leu624Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.67
T
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.0
D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0040
D
Sift4G
Pathogenic
0.0010
D
Polyphen
0.98
D
Vest4
0.94
MutPred
0.95
Loss of stability (P = 0.0159);
MVP
0.99
MPC
0.20
ClinPred
0.97
D
GERP RS
4.2
Varity_R
0.69
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1929555187; hg19: chrX-8502473; API