dbSNP rs808119: ANOS1:p.Val534Phe (chrX-8536792-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000216.4(ANOS1):c.1600G>T(p.Val534Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V534I) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

ANOS1
NM_000216.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.456

Publications

31 publications found

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 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 1 with or without anosmia
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ANOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053531468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANOS1	NM_000216.4 link	c.1600G>T	p.Val534Phe	missense_variant	Exon 11 of 14	ENST00000262648.8	NP_000207.2	P23352

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8 link	c.1600G>T	p.Val534Phe	missense_variant	Exon 11 of 14	1	NM_000216.4	ENSP00000262648.3		P23352
ANOS1	ENST00000481896.1 link	n.145G>T		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000566

AC:

AN:

176751

AF XY:

0.0000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000372

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.13e-7

AC:

AN:

1095281

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360861

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26362

American (AMR)

AF:

0.0000286

AC:

AN:

34954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19356

East Asian (EAS)

AF:

0.00

AC:

AN:

30127

South Asian (SAS)

AF:

0.00

AC:

AN:

53804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40407

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840167

Other (OTH)

AF:

0.00

AC:

AN:

45977

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.038

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.57

M_CAP

Benign

0.054

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

PhyloP100

-0.46

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.7

REVEL

Benign

0.10

Sift

Benign

0.28

Sift4G

Benign

0.55

Polyphen

0.0050

Vest4

0.15

MutPred

0.26

Loss of ubiquitination at K532 (P = 0.1106);

MVP

0.11

MPC

0.14

ClinPred

0.035

GERP RS

-4.1

Varity_R

0.11

gMVP

0.51

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over