X-8534355-A-CG

Position:

• chrX-8534355-A-CG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000216.4(ANOS1):​c.1948delinsCG​(p.Phe650ArgfsTer17) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ANOS1 NM_000216.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.63

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 6 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. Fraction of 0.0465 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-8534355-A-CG is Pathogenic according to our data. Variant chrX-8534355-A-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3256568.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.1948delinsCG	p.Phe650ArgfsTer17	frameshift_variant	13/14	ENST00000262648.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.1948delinsCG	p.Phe650ArgfsTer17	frameshift_variant	13/14	1	NM_000216.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Sep 18, 2023

PVS1, PM2 - The variant is expected to result in an absent or disrupted protein product. Low frequency in gnomAD population databases. -

Computational scores

Source: dbNSFP v4.3

Splicing

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-8502396;