rs773138384

Variant names:

• chrX-8699693-C-T
• rs773138384
• NM_000216.4:c.255+5G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_000216.4(ANOS1):​c.255+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,189,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.0000074 (0 hom. 3 hem.)
• Consequence: ANOS1 NM_000216.4 splice_region, intron
• Scores: Splicing: ADA: 0.6174
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.46
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae)
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP5: Variant X-8699693-C-T is Pathogenic according to our data. Variant chrX-8699693-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 427743.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 8 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANOS1	NM_000216.4	c.255+5G>A		splice_region_variant, intron_variant	Intron 2 of 13	ENST00000262648.8	NP_000207.2
ANOS1	NM_001440775.1	c.255+5G>A		splice_region_variant, intron_variant	Intron 2 of 8		NP_001427704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANOS1	ENST00000262648.8	c.255+5G>A		splice_region_variant, intron_variant	Intron 2 of 13	1	NM_000216.4	ENSP00000262648.3

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111680 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.0000279 AC: 5 AN: 179524 AF XY: 0.0000311

Gnomad AFR exome AF: 0.000231

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000743 AC: 8 AN: 1077406 Hom.: 0 Cov.: 25 AF XY: 0.00000867 AC XY: 3 AN XY: 345978

African (AFR) AF: 0.0000771 AC: 2 AN: 25929

American (AMR) AF: 0.00 AC: 0 AN: 34863

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18871

East Asian (EAS) AF: 0.00 AC: 0 AN: 29389

South Asian (SAS) AF: 0.0000940 AC: 5 AN: 53203

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39333

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3992

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826815

Other (OTH) AF: 0.0000222 AC: 1 AN: 45011

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111680 Hom.: 0 Cov.: 23 AF XY: 0.0000886 AC XY: 3 AN XY: 33850

African (AFR) AF: 0.000130 AC: 4 AN: 30775

American (AMR) AF: 0.00 AC: 0 AN: 10487

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3581

South Asian (SAS) AF: 0.00 AC: 0 AN: 2644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5963

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53145

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jul 27, 2025

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant NM_000216.4(ANOS1):c.255+5G>A has low population frequency (GnomAD 4.1.0 AF 0.00001009) with 12 genotyped alleles (6 hemizygotes). This variant is not previously described in the literature. Other cases in internal databases (including males) carry this variant with no ANOS1 phenotype detected. -

Apr 27, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Homozygous mutation was confirmed -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	18
DANN	Benign	0.55
PhyloP100		3.5
Mutation Taster		=98/2	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
dbscSNV1_RF	Benign	0.59
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

Other links and lift over

dbSNP: rs773138384; hg19: chrX-8667734;