NM_000216.4:c.409C>G

Variant names:

• chrX-8597166-G-C
• rs1043292415
• NM_000216.4:c.409C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000216.4(ANOS1):​c.409C>G​(p.Pro137Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,209,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B: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: 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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• BP6: Variant X-8597166-G-C is Benign according to our data. Variant chrX-8597166-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 463528.

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.409C>G	p.Pro137Ala	missense	Exon 4 of 14	NP_000207.2	P23352
	ANOS1	NM_001440775.1		c.409C>G	p.Pro137Ala	missense	Exon 4 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.409C>G	p.Pro137Ala	missense	Exon 4 of 14	ENSP00000262648.3	P23352
	ANOS1	ENST00000921740.1		c.409C>G	p.Pro137Ala	missense	Exon 4 of 14	ENSP00000591799.1
	ANOS1	ENST00000921741.1		c.409C>G	p.Pro137Ala	missense	Exon 4 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111790 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

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: 0.00000273 AC: 3 AN: 1098019 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363393

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841985

Other (OTH) AF: 0.0000651 AC: 3 AN: 46087

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111790 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33970

African (AFR) AF: 0.00 AC: 0 AN: 30744

American (AMR) AF: 0.000286 AC: 3 AN: 10506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53214

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.80	N
PhyloP100		6.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.58
Sift	Benign	0.095	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.34
MutPred		0.70		Loss of glycosylation at P137 (P = 0.0567)
MVP		0.99
MPC		2.0
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.20
gMVP		0.57
Mutation Taster		=68/32	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: rs1043292415; hg19: chrX-8565207;