dbSNP rs199652310: ANOS1:p.Pro644Pro (chrX-8534371-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000216.4(ANOS1):c.1932G>A(p.Pro644Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,208,955 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000027 ( 0 hom. 8 hem. )

Consequence

ANOS1
NM_000216.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.26

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: 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant X-8534371-C-T is Benign according to our data. Variant chrX-8534371-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 731395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.26 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000273 (30/1097546) while in subpopulation AMR AF = 0.000511 (18/35192). AF 95% confidence interval is 0.00033. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 5 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.1932G>A	p.Pro644Pro	synonymous	Exon 13 of 14	NP_000207.2	P23352

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANOS1	ENST00000262648.8	TSL:1 MANE Select	c.1932G>A	p.Pro644Pro	synonymous	Exon 13 of 14	ENSP00000262648.3	P23352
ANOS1	ENST00000921740.1		c.1929G>A	p.Pro643Pro	synonymous	Exon 13 of 14	ENSP00000591799.1
ANOS1	ENST00000921741.1		c.1785G>A	p.Pro595Pro	synonymous	Exon 12 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000382

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

GnomAD2 exomes

AF:

0.0000657

AC:

AN:

182649

AF XY:

0.0000893

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.000365

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:

0.000222

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1097546

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

362906

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

26387

American (AMR)

AF:

0.000511

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

54095

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841564

Other (OTH)

AF:

0.0000434

AC:

AN:

46073

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.0000449

AC:

AN:

111409

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33615

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30679

American (AMR)

AF:

0.000382

AC:

AN:

10470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3512

South Asian (SAS)

AF:

0.00

AC:

AN:

2609

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53058

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000642

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypogonadotropic hypogonadism 1 with or without anosmia (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.039

(source)

DANN

Benign

0.64

PhyloP100

-1.3

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over