Genetic Variant NM_000216.4:c.109G>A (chrX-8731928-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000216.4(ANOS1):c.109G>A(p.Glu37Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000386 in 1,036,780 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000039 ( 0 hom. 0 hem. )

Consequence

ANOS1
NM_000216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3355495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANOS1	NM_000216.4 link	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 14	ENST00000262648.8	NP_000207.2
ANOS1	NM_001440775.1 link	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 9		NP_001427704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8 link	c.109G>A	p.Glu37Lys	missense_variant	Exon 1 of 14	1	NM_000216.4	ENSP00000262648.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000386

AC:

AN:

1036780

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

332708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22123

American (AMR)

AF:

0.00

AC:

AN:

26676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17663

East Asian (EAS)

AF:

0.00

AC:

AN:

24726

South Asian (SAS)

AF:

0.00

AC:

AN:

47790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36938

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2758

European-Non Finnish (NFE)

AF:

0.00000491

AC:

AN:

814871

Other (OTH)

AF:

0.00

AC:

AN:

43235

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia

Uncertain:1

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.66

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.40

MutationAssessor

Benign

2.0

PhyloP100

2.3

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.74

REVEL

Benign

0.24

Sift

Benign

0.030

Sift4G

Uncertain

0.025

Vest4

0.15

ClinPred

0.86

GERP RS

2.6

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.089

gMVP

0.48

Mutation Taster

=95/5

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over