X-8534399-T-G

Variant names:

• chrX-8534399-T-G
• rs1057519418
• NM_000216.4:c.1904A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000216.4(ANOS1):​c.1904A>C​(p.Gln635Pro) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.58
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae)
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant X-8534399-T-G is Pathogenic according to our data. Variant chrX-8534399-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375418.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANOS1	NM_000216.4	c.1904A>C	p.Gln635Pro	missense_variant	Exon 13 of 14	ENST00000262648.8	NP_000207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8	c.1904A>C	p.Gln635Pro	missense_variant	Exon 13 of 14	1	NM_000216.4	ENSP00000262648.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia Pathogenic:1

Jan 03, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.87
gMVP		0.97
Mutation Taster		=71/29	disease causing (ClinVar)

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: rs1057519418; hg19: chrX-8502440;