X-8534412-GG-AA

Position:

• chrX-8534412-GG-AA

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.1890_1891delinsTT​(p.Arg631Ter) variant causes a stop gained change involving the alteration of a non-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: 22)
• Consequence: ANOS1 NM_000216.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.28

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 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-8534412-GG-AA is Pathogenic according to our data. Variant chrX-8534412-GG-AA is described in ClinVar as [Pathogenic]. Clinvar id is 1069737.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.1890_1891delinsTT	p.Arg631Ter	stop_gained	13/14	ENST00000262648.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.1890_1891delinsTT	p.Arg631Ter	stop_gained	13/14	1	NM_000216.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

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

Feb 27, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ANOS1 are known to be pathogenic (PMID: 8504298, 11297579). This nonsense change has been reported in the literature in individuals with Kallmann Syndrome (PMID: 11044805). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg631*) in the ANOS1 gene. It is expected to result in an absent or disrupted protein product. -

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-8502453;