Variant chrX-8539744-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000216.4(ANOS1):c.1369C>T(p.Arg457*) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

ANOS1
NM_000216.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-8539744-G-A is Pathogenic according to our data. Variant chrX-8539744-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANOS1	NM_000216.4 linkuse as main transcript	c.1369C>T	p.Arg457*	stop_gained	10/14	ENST00000262648.8	NP_000207.2	P23352

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8 linkuse as main transcript	c.1369C>T	p.Arg457*	stop_gained	10/14	1	NM_000216.4	ENSP00000262648.3		P23352

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1098123

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363485

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 02, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Kallman syndrome (PMID: 11297579, 23643382). ClinVar contains an entry for this variant (Variation ID: 180157). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg457*) in the ANOS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANOS1 are known to be pathogenic (PMID: 8504298, 11297579). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Nov 27, 2023	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PM2;PS2;PVS1 -

Hypogonadotropic hypogonadism 7 with or without anosmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

Delayed puberty

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.23

Vest4

0.17

GERP RS

2.6

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over