NM_000216.4:c.1187C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000216.4(ANOS1):c.1187C>T(p.Ser396Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,208,393 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 105 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., 13 hem., cov: 23)

Exomes 𝑓: 0.00022 ( 0 hom. 92 hem. )

Consequence

ANOS1
NM_000216.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:2

Conservation

PhyloP100: 4.06

Publications

11 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: Labcorp Genetics (formerly Invitae), ClinGen
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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09063691).

BP6

Variant X-8568252-G-A is Benign according to our data. Variant chrX-8568252-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10013.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000404 (45/111386) while in subpopulation AMR AF = 0.00182 (19/10456). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 45 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANOS1	NM_000216.4	MANE Select	c.1187C>T	p.Ser396Leu	missense	Exon 8 of 14	NP_000207.2	P23352
	ANOS1	NM_001440775.1		c.1187C>T	p.Ser396Leu	missense	Exon 8 of 9	NP_001427704.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANOS1	ENST00000262648.8	TSL:1 MANE Select	c.1187C>T	p.Ser396Leu	missense	Exon 8 of 14	ENSP00000262648.3	P23352
ANOS1	ENST00000921740.1		c.1187C>T	p.Ser396Leu	missense	Exon 8 of 14	ENSP00000591799.1
ANOS1	ENST00000921741.1		c.1187C>T	p.Ser396Leu	missense	Exon 8 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes

AF:

0.000404

AC:

AN:

111333

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00182

Gnomad ASJ

AF:

0.00415

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000169

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.000292

AC:

AN:

181668

AF XY:

0.000166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000366

Gnomad ASJ exome

AF:

0.00403

Gnomad EAS exome

AF:

0.0000725

Gnomad FIN exome

AF:

0.0000630

Gnomad NFE exome

AF:

0.0000866

Gnomad OTH exome

AF:

0.000445

GnomAD4 exome

AF:

0.000223

AC:

245

AN:

1097007

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

AN XY:

362433

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26390

American (AMR)

AF:

0.000540

AC:

AN:

35183

Ashkenazi Jewish (ASJ)

AF:

0.00506

AC:

AN:

19364

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30186

South Asian (SAS)

AF:

0.0000555

AC:

AN:

54007

European-Finnish (FIN)

AF:

0.0000494

AC:

AN:

40493

Middle Eastern (MID)

AF:

0.000726

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000111

AC:

AN:

841200

Other (OTH)

AF:

0.000565

AC:

AN:

46050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.000404

AC:

AN:

111386

Hom.:

Cov.:

AF XY:

0.000387

AC XY:

AN XY:

33618

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30667

American (AMR)

AF:

0.00182

AC:

AN:

10456

Ashkenazi Jewish (ASJ)

AF:

0.00415

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3520

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.000170

AC:

AN:

53096

Other (OTH)

AF:

0.00331

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000353

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000214

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypogonadotropic hypogonadism 1 with or without anosmia (2)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.2

PhyloP100

4.1

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.46

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0050

Polyphen

0.62

Vest4

0.096

MVP

0.70

MPC

0.19

ClinPred

0.057

GERP RS

3.0

Varity_R

0.19

gMVP

0.62

Mutation Taster

=91/9

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over