X-8532999-T-C

Variant names:

• chrX-8532999-T-C
• rs2146784839
• NM_000216.4:c.2039A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000216.4(ANOS1):​c.2039A>G​(p.Tyr680Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000962 in 1,039,870 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: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12939015).

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.2039A>G	p.Tyr680Cys	missense	Exon 14 of 14	NP_000207.2	P23352

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANOS1	ENST00000262648.8	TSL:1 MANE Select	c.2039A>G	p.Tyr680Cys	missense	Exon 14 of 14	ENSP00000262648.3	P23352
	ANOS1	ENST00000921740.1		c.2036A>G	p.Tyr679Cys	missense	Exon 14 of 14	ENSP00000591799.1
	ANOS1	ENST00000921741.1		c.1892A>G	p.Tyr631Cys	missense	Exon 13 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.62e-7 AC: 1 AN: 1039870 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 320332

African (AFR) AF: 0.00 AC: 0 AN: 25288

American (AMR) AF: 0.00 AC: 0 AN: 35143

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19010

East Asian (EAS) AF: 0.00 AC: 0 AN: 29986

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40469

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4021

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 789072

Other (OTH) AF: 0.00 AC: 0 AN: 44142

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.011	B
Vest4		0.48
MutPred		0.25		Loss of phosphorylation at Y680 (P = 0.013)
MVP		0.27
MPC		0.59
ClinPred		0.78	D
GERP RS		1.3
Varity_R		0.20
gMVP		0.61
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs2146784839; hg19: chrX-8501040;