rs1555904582

Variant names:

• chrX-8731879-C-T
• rs1555904582
• NM_000216.4:c.158G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000216.4(ANOS1):​c.158G>A​(p.Cys53Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C53R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.91
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

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.158G>A	p.Cys53Tyr	missense	Exon 1 of 14	NP_000207.2	P23352
	ANOS1	NM_001440775.1		c.158G>A	p.Cys53Tyr	missense	Exon 1 of 9	NP_001427704.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANOS1	ENST00000262648.8	TSL:1 MANE Select	c.158G>A	p.Cys53Tyr	missense	Exon 1 of 14	ENSP00000262648.3	P23352
	ANOS1	ENST00000921740.1		c.158G>A	p.Cys53Tyr	missense	Exon 1 of 14	ENSP00000591799.1
	ANOS1	ENST00000921741.1		c.158G>A	p.Cys53Tyr	missense	Exon 1 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1079955 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 353505

African (AFR) AF: 0.00 AC: 0 AN: 24381

American (AMR) AF: 0.00 AC: 0 AN: 34110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18818

East Asian (EAS) AF: 0.00 AC: 0 AN: 28560

South Asian (SAS) AF: 0.00 AC: 0 AN: 52283

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38813

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 834969

Other (OTH) AF: 0.00 AC: 0 AN: 45173

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hypogonadotropic hypogonadism 1 with or without anosmia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.69	P
Vest4		0.74
MutPred		0.72		Loss of catalytic residue at L54 (P = 0.0151)
MVP		0.95
MPC		2.5
ClinPred		0.99	D
GERP RS		2.7
PromoterAI		-0.074	Neutral
Varity_R		0.72
gMVP		0.98
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555904582; hg19: chrX-8699920;