X-8536860-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000216.4(ANOS1):c.1532C>A(p.Ser511Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,205,846 control chromosomes in the GnomAD database, including 4 homozygotes. There are 713 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 32 hem., cov: 22)
  • Exomes 𝑓: 0.0017 (4 hom. 681 hem.)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:5
• Conservation: PhyloP100: 2.50

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012378961).
• BP6: Variant X-8536860-G-T is Benign according to our data. Variant chrX-8536860-G-T is described in ClinVar as [Benign]. Clinvar id is 463525.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-8536860-G-T is described in Lovd as [Likely_benign]. Variant chrX-8536860-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00106 (118/111661) while in subpopulation SAS AF= 0.00227 (6/2644). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 32 XL,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANOS1	NM_000216.4	c.1532C>A	p.Ser511Tyr	missense_variant	11/14	ENST00000262648.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.1532C>A	p.Ser511Tyr	missense_variant	11/14	1	NM_000216.4	P1
ANOS1	ENST00000481896.1	n.77C>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 118 AN: 111609 Hom.: 0 Cov.: 22 AF XY: 0.000947 AC XY: 32 AN XY: 33795

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.00149 AC: 271 AN: 181586 Hom.: 0 AF XY: 0.00200 AC XY: 132 AN XY: 66106

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000512

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00173 AC: 1892 AN: 1094185 Hom.: 4 Cov.: 30 AF XY: 0.00189 AC XY: 681 AN XY: 359629

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00106 AC: 118 AN: 111661 Hom.: 0 Cov.: 22 AF XY: 0.000945 AC XY: 32 AN XY: 33857

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00227

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.000657

Alfa AF: 0.00167 Hom.: 18

Bravo AF: 0.00121

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.00175 AC: 212

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hypogonadotropic hypogonadism 1 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	6.2
Dann	Benign	0.099
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.15	B
Vest4		0.19
MVP		0.082
MPC		0.17
ClinPred		0.016	T
GERP RS		0.46
Varity_R		0.067
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs142729431; hg19: chrX-8504901;