Genetic Variant ANOS1:c.1984+138delC (chrX-8534180-AG-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000216.4(ANOS1):c.1984+138delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 111,365 control chromosomes in the GnomAD database, including 7 homozygotes. There are 389 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 7 hom., 389 hem., cov: 21)

Exomes 𝑓: 0.015 ( 69 hom. 2343 hem. )

Failed GnomAD Quality Control

Consequence

ANOS1
NM_000216.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.614

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 -10 ACMG points.

BP6

Variant X-8534180-AG-A is Benign according to our data. Variant chrX-8534180-AG-A is described in ClinVar as Benign. ClinVar VariationId is 1238821.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1374/111365) while in subpopulation NFE AF = 0.0187 (991/52978). AF 95% confidence interval is 0.0177. There are 7 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High AC in GnomAd4 at 1374 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.1984+138delC		intron	N/A	NP_000207.2	P23352

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ANOS1	ENST00000262648.8	TSL:1 MANE Select	c.1984+138delC	intron	N/A	ENSP00000262648.3	P23352
ANOS1	ENST00000921740.1		c.1981+138delC	intron	N/A	ENSP00000591799.1
ANOS1	ENST00000921741.1		c.1837+138delC	intron	N/A	ENSP00000591800.1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1374

AN:

111319

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00173

Gnomad AMI

AF:

0.0306

Gnomad AMR

AF:

0.00352

Gnomad ASJ

AF:

0.00454

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00153

Gnomad FIN

AF:

0.0405

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.0106

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0153

AC:

7948

AN:

518516

Hom.:

AF XY:

0.0151

AC XY:

2343

AN XY:

154850

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

14586

American (AMR)

AF:

0.00260

AC:

AN:

26200

Ashkenazi Jewish (ASJ)

AF:

0.00412

AC:

AN:

14088

East Asian (EAS)

AF:

0.00

AC:

AN:

24987

South Asian (SAS)

AF:

0.00201

AC:

AN:

36263

European-Finnish (FIN)

AF:

0.0434

AC:

1270

AN:

29276

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

1900

European-Non Finnish (NFE)

AF:

0.0178

AC:

6143

AN:

344611

Other (OTH)

AF:

0.0115

AC:

305

AN:

26605

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

291

581

872

1162

1453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<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:

0.0123

AC:

1374

AN:

111365

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

389

AN XY:

33529

show subpopulations

African (AFR)

AF:

0.00172

AC:

AN:

30734

American (AMR)

AF:

0.00352

AC:

AN:

10518

Ashkenazi Jewish (ASJ)

AF:

0.00454

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00154

AC:

AN:

2603

European-Finnish (FIN)

AF:

0.0405

AC:

240

AN:

5924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0187

AC:

991

AN:

52978

Other (OTH)

AF:

0.0105

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0127

Hom.:

Bravo

AF:

0.00915

Asia WGS

AF:

0.000398

AC:

AN:

2520

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over