rs137852517

chrX-8568252-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000216.4(ANOS1):c.1187C>T(p.Ser396Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,208,393 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 105 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., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00022 (0 hom. 92 hem.)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 4.06

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09063691).
• BP6: Variant X-8568252-G-A is Benign according to our data. Variant chrX-8568252-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10013.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000404 (45/111386) while in subpopulation AMR AF= 0.00182 (19/10456). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 13 XL,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANOS1	NM_000216.4	c.1187C>T	p.Ser396Leu	missense_variant	8/14	ENST00000262648.8
ANOS1	XM_005274501.5	c.1187C>T	p.Ser396Leu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.1187C>T	p.Ser396Leu	missense_variant	8/14	1	NM_000216.4	P1
ANOS1	ENST00000488294.1	n.277C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.000404 AC: 45 AN: 111333 Hom.: 0 Cov.: 23 AF XY: 0.000387 AC XY: 13 AN XY: 33555

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00182

Gnomad ASJ AF: 0.00415

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000292 AC: 53 AN: 181668 Hom.: 0 AF XY: 0.000166 AC XY: 11 AN XY: 66232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000366

Gnomad ASJ exome AF: 0.00403

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.0000630

Gnomad NFE exome AF: 0.0000866

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000223 AC: 245 AN: 1097007 Hom.: 0 Cov.: 30 AF XY: 0.000254 AC XY: 92 AN XY: 362433

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000540

Gnomad4 ASJ exome AF: 0.00506

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000555

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.000565

GnomAD4 genome AF: 0.000404 AC: 45 AN: 111386 Hom.: 0 Cov.: 23 AF XY: 0.000387 AC XY: 13 AN XY: 33618

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00182

Gnomad4 ASJ AF: 0.00415

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000170

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000323 Hom.: 9

Bravo AF: 0.000763

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 1 with or without anosmia Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 20, 2006	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

ANOS1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.4e-11	A
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.62	P
Vest4		0.096
MVP		0.70
MPC		0.19
ClinPred		0.057	T
GERP RS		3.0
Varity_R		0.19
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852517; hg19: chrX-8536293; COSMIC: COSV52915476;