Variant rs137852514 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000216.4(ANOS1):c.774G>C(p.Trp258Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,209,446 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

ANOS1
NM_000216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANOS1	NM_000216.4 linkuse as main transcript	c.774G>C	p.Trp258Cys	missense_variant	6/14	ENST00000262648.8	NP_000207.2	P23352
ANOS1	XM_005274501.5 linkuse as main transcript	c.774G>C	p.Trp258Cys	missense_variant	6/9		XP_005274558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8 linkuse as main transcript	c.774G>C	p.Trp258Cys	missense_variant	6/14	1	NM_000216.4	ENSP00000262648.3		P23352

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34288

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097318

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362746

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34288

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2024

The c.774G>C (p.W258C) alteration is located in exon 6 (coding exon 6) of the ANOS1 gene. This alteration results from a G to C substitution at nucleotide position 774, causing the tryptophan (W) at amino acid position 258 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.5

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-11

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.81

MutPred

0.66

Loss of MoRF binding (P = 0.0138);

MVP

0.87

MPC

2.4

ClinPred

1.0

GERP RS

3.7

Varity_R

0.92

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over