rs809446

chrX-8535600-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000216.4(ANOS1):c.1833C>T(p.Ile611=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (12116 hom., 17436 hem., cov: 23)
  • Exomes 𝑓: 0.62 (147868 hom. 220049 hem.)
  • Failed GnomAD Quality Control
• Consequence: ANOS1 NM_000216.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.356

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-8535600-G-A is Benign according to our data. Variant chrX-8535600-G-A is described in ClinVar as [Benign]. Clinvar id is 255564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-8535600-G-A is described in Lovd as [Benign]. Variant chrX-8535600-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.356 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 12123 XL,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANOS1	NM_000216.4	c.1833C>T	p.Ile611=	synonymous_variant	12/14	ENST00000262648.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.1833C>T	p.Ile611=	synonymous_variant	12/14	1	NM_000216.4	P1
ANOS1	ENST00000481896.1	n.378C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.535 AC: 59407 AN: 110963 Hom.: 12123 Cov.: 23 AF XY: 0.525 AC XY: 17430 AN XY: 33225

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.610

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.555

GnomAD3 exomes AF: 0.555 AC: 100457 AN: 180887 Hom.: 18903 AF XY: 0.559 AC XY: 36673 AN XY: 65621

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.657

Gnomad EAS exome AF: 0.655

Gnomad SAS exome AF: 0.403

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.658

Gnomad OTH exome AF: 0.594

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.624 AC: 680341 AN: 1090675 Hom.: 147868 Cov.: 29 AF XY: 0.616 AC XY: 220049 AN XY: 357275

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.371

Gnomad4 ASJ exome AF: 0.652

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.588

Gnomad4 NFE exome AF: 0.659

Gnomad4 OTH exome AF: 0.607

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.535 AC: 59394 AN: 111017 Hom.: 12116 Cov.: 23 AF XY: 0.524 AC XY: 17436 AN XY: 33289

Gnomad4 AFR AF: 0.331

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.653

Gnomad4 SAS AF: 0.377

Gnomad4 FIN AF: 0.585

Gnomad4 NFE AF: 0.654

Gnomad4 OTH AF: 0.558

Alfa AF: 0.532 Hom.: 12167

Bravo AF: 0.523

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypogonadotropic hypogonadism 1 with or without anosmia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.20
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs809446; hg19: chrX-8503641; COSMIC: COSV52922613;