chrX-8534440-C-CA

Position:

• chrX-8534440-C-CA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000216.4(ANOS1):​c.1862_1863insT​(p.Pro622AlafsTer45) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ANOS1 NM_000216.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-8534440-C-CA is Pathogenic according to our data. Variant chrX-8534440-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 1460215.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANOS1	NM_000216.4	c.1862_1863insT	p.Pro622AlafsTer45	frameshift_variant	13/14	ENST00000262648.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.1862_1863insT	p.Pro622AlafsTer45	frameshift_variant	13/14	1	NM_000216.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2021

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 creates a premature translational stop signal (p.Pro622Alafs*45) in the ANOS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the ANOS1 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the ANOS1 protein. Other variant(s) that disrupt this region (p.Arg631*) have been determined to be pathogenic (PMID: 11044805). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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-8502481;