chrX-8553929-ATAAG-A

Variant names:

• chrX-8553929-ATAAG-A
• rs201866844
• NM_000216.4:c.1354+19_1354+22delCTTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000216.4(ANOS1):​c.1354+19_1354+22delCTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00748 in 1,187,970 control chromosomes in the GnomAD database, including 411 homozygotes. There are 2,314 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (208 hom., 1137 hem., cov: 21)
  • Exomes 𝑓: 0.0043 (203 hom. 1177 hem.)
• Consequence: ANOS1 NM_000216.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0330
• 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: Labcorp Genetics (formerly Invitae), ClinGen
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-8553929-ATAAG-A is Benign according to our data. Variant chrX-8553929-ATAAG-A is described in ClinVar as Benign. ClinVar VariationId is 516595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

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.1354+19_1354+22delCTTA		intron	N/A	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.1354+19_1354+22delCTTA		intron	N/A	ENSP00000262648.3	P23352
	ANOS1	ENST00000921740.1		c.1351+19_1351+22delCTTA		intron	N/A	ENSP00000591799.1
	ANOS1	ENST00000921741.1		c.1208-14175_1208-14172delCTTA		intron	N/A	ENSP00000591800.1

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 4255 AN: 111959 Hom.: 207 Cov.: 21

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00889

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000744

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0271

GnomAD2 exomes AF: 0.0106 AC: 1932 AN: 182742 AF XY: 0.00688

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000368

Gnomad OTH exome AF: 0.00421

GnomAD4 exome AF: 0.00428 AC: 4610 AN: 1075962 Hom.: 203 AF XY: 0.00342 AC XY: 1177 AN XY: 343952

African (AFR) AF: 0.142 AC: 3673 AN: 25932

American (AMR) AF: 0.00631 AC: 222 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19243

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30116

South Asian (SAS) AF: 0.000429 AC: 23 AN: 53644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.0123 AC: 50 AN: 4077

European-Non Finnish (NFE) AF: 0.000190 AC: 156 AN: 821917

Other (OTH) AF: 0.0107 AC: 485 AN: 45375

GnomAD4 genome AF: 0.0382 AC: 4278 AN: 112008 Hom.: 208 Cov.: 21 AF XY: 0.0332 AC XY: 1137 AN XY: 34208

African (AFR) AF: 0.134 AC: 4121 AN: 30677

American (AMR) AF: 0.00888 AC: 94 AN: 10590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.000747 AC: 2 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6113

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.000338 AC: 18 AN: 53291

Other (OTH) AF: 0.0268 AC: 41 AN: 1532

Alfa AF: 0.0203 Hom.: 111

Bravo AF: 0.0446

Asia WGS AF: 0.0110 AC: 28 AN: 2522

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypogonadotropic hypogonadism 1 with or without anosmia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.033
Mutation Taster		=100/0	polymorphism (auto)

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: rs201866844; hg19: chrX-8521970;