rs199771303

Variant names:

• chrX-8533023-T-C
• rs199771303
• NM_000216.4:c.2015A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000216.4(ANOS1):​c.2015A>G​(p.His672Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,170,607 control chromosomes in the GnomAD database, including 1 homozygotes. There are 112 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 16 hem., cov: 22)
  • Exomes 𝑓: 0.00027 (1 hom. 96 hem.)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.16
• Publications: 4 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1433368).
• BP6: Variant X-8533023-T-C is Benign according to our data. Variant chrX-8533023-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224350.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0004 (45/112406) while in subpopulation NFE AF = 0.000675 (36/53311). AF 95% confidence interval is 0.000501. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 45 XL,AD gene.

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.2015A>G	p.His672Arg	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.2015A>G	p.His672Arg	missense	Exon 14 of 14	ENSP00000262648.3	P23352
	ANOS1	ENST00000921740.1		c.2012A>G	p.His671Arg	missense	Exon 14 of 14	ENSP00000591799.1
	ANOS1	ENST00000921741.1		c.1868A>G	p.His623Arg	missense	Exon 13 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 45 AN: 112356 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.000326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000675

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000280 AC: 51 AN: 181953 AF XY: 0.000255

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000629

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000275 AC: 291 AN: 1058201 Hom.: 1 Cov.: 23 AF XY: 0.000290 AC XY: 96 AN XY: 331339

African (AFR) AF: 0.0000390 AC: 1 AN: 25666

American (AMR) AF: 0.000171 AC: 6 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19123

East Asian (EAS) AF: 0.00 AC: 0 AN: 30040

South Asian (SAS) AF: 0.000245 AC: 13 AN: 53119

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40484

Middle Eastern (MID) AF: 0.000495 AC: 2 AN: 4040

European-Non Finnish (NFE) AF: 0.000324 AC: 261 AN: 805803

Other (OTH) AF: 0.000179 AC: 8 AN: 44769

GnomAD4 genome AF: 0.000400 AC: 45 AN: 112406 Hom.: 0 Cov.: 22 AF XY: 0.000463 AC XY: 16 AN XY: 34566

African (AFR) AF: 0.000129 AC: 4 AN: 30967

American (AMR) AF: 0.000188 AC: 2 AN: 10621

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3580

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2705

European-Finnish (FIN) AF: 0.000326 AC: 2 AN: 6133

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000675 AC: 36 AN: 53311

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.000453 Hom.: 5

Bravo AF: 0.000321

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000214 AC: 26

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	-	Amenorrhea (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Benign	0.058	T
Sift4G	Uncertain	0.019	D
Polyphen		0.95	P
Vest4		0.15
MVP		0.59
MPC		0.56
ClinPred		0.17	T
GERP RS		3.8
Varity_R		0.43
gMVP		0.37
Mutation Taster		=96/4	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: rs199771303; hg19: chrX-8501064; COSMIC: COSV106090607; COSMIC: COSV106090607;