rs137852513

Positions:

• chrX-8585354-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000216.4(ANOS1):​c.769C>T​(p.Arg257*) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ANOS1 NM_000216.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.02

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 Pathogenic. Variant got 12 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-8585354-G-A is Pathogenic according to our data. Variant chrX-8585354-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10004.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-8585354-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANOS1	NM_000216.4	c.769C>T	p.Arg257*	stop_gained	6/14	ENST00000262648.8	NP_000207.2
ANOS1	XM_005274501.5	c.769C>T	p.Arg257*	stop_gained	6/9		XP_005274558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8	c.769C>T	p.Arg257*	stop_gained	6/14	1	NM_000216.4	ENSP00000262648.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1097209 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362647

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 10004). This premature translational stop signal has been observed in individual(s) with Kallman syndrome and bilateral kidney agenesis (PMID: 1518845, 22035731, 28566479). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg257*) 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, no assertion criteria provided	literature only	OMIM	Sep 01, 1992	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.60	D
Vest4		0.58
GERP RS		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs137852513; hg19: chrX-8553395;