rs1043292415

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP3BP6

The NM_000216.4(ANOS1):c.409C>G(p.Pro137Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,209,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

ANOS1
NM_000216.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.58

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain WAP (size 49) in uniprot entity KALM_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_000216.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

BP6

Variant X-8597166-G-C is Benign according to our data. Variant chrX-8597166-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463528.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANOS1	NM_000216.4 linkuse as main transcript	c.409C>G	p.Pro137Ala	missense_variant	4/14	ENST00000262648.8
ANOS1	XM_005274501.5 linkuse as main transcript	c.409C>G	p.Pro137Ala	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8 linkuse as main transcript	c.409C>G	p.Pro137Ala	missense_variant	4/14	1	NM_000216.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33970

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098019

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363393

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:

0.00

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33970

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000286

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.409C>G (p.P137A) alteration is located in exon 4 (coding exon 4) of the ANOS1 gene. This alteration results from a C to G substitution at nucleotide position 409, causing the proline (P) at amino acid position 137 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hypogonadotropic hypogonadism 1 with or without anosmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.80

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.58

Sift

Benign

0.095

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.34

MutPred

0.70

Loss of glycosylation at P137 (P = 0.0567);

MVP

0.99

MPC

2.0

ClinPred

0.98

GERP RS

4.5

Varity_R

0.20

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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