X-8535755-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000216.4(ANOS1):c.1678G>A(p.Val560Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,210,346 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 91 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00022 ( 0 hom. 82 hem. )

Consequence

ANOS1
NM_000216.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.732

Publications

7 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009019673).

BP6

Variant X-8535755-C-T is Benign according to our data. Variant chrX-8535755-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225397.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00024 (27/112417) while in subpopulation EAS AF = 0.00732 (26/3552). AF 95% confidence interval is 0.00513. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 27 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000216.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANOS1	NM_000216.4	MANE Select	c.1678G>A	p.Val560Ile	missense	Exon 12 of 14	NP_000207.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANOS1	ENST00000262648.8	TSL:1 MANE Select	c.1678G>A	p.Val560Ile	missense	Exon 12 of 14	ENSP00000262648.3
ANOS1	ENST00000921740.1		c.1675G>A	p.Val559Ile	missense	Exon 12 of 14	ENSP00000591799.1
ANOS1	ENST00000921741.1		c.1531G>A	p.Val511Ile	missense	Exon 11 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes

AF:

0.000240

AC:

AN:

112363

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00730

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000867

AC:

159

AN:

183362

AF XY:

0.000796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000218

AC:

239

AN:

1097929

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

AN XY:

363285

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26397

American (AMR)

AF:

0.0000568

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00699

AC:

211

AN:

30204

South Asian (SAS)

AF:

0.000129

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841840

Other (OTH)

AF:

0.000347

AC:

AN:

46089

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.000240

AC:

AN:

112417

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

AN XY:

34613

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30958

American (AMR)

AF:

0.00

AC:

AN:

10661

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00732

AC:

AN:

3552

South Asian (SAS)

AF:

0.00

AC:

AN:

2728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53290

Other (OTH)

AF:

0.00

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000510

ExAC

AF:

0.000758

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypogonadotropic hypogonadism 1 with or without anosmia (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.95

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.081

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.73

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.20

REVEL

Benign

0.20

Sift

Benign

0.42

Sift4G

Benign

0.38

Polyphen

0.17

Vest4

0.011

MutPred

0.51

Loss of catalytic residue at V560 (P = 0.0646)

MVP

0.59

MPC

0.086

ClinPred

0.015

GERP RS

0.37

Varity_R

0.028

gMVP

0.076

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over