chrX-8533079-C-A

Variant names:

• chrX-8533079-C-A
• rs41303179
• NM_000216.4:c.1985-26G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000216.4(ANOS1):​c.1985-26G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 953,021 control chromosomes in the GnomAD database, including 29,369 homozygotes. There are 83,369 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.30 (3873 hom., 9871 hem., cov: 23)
  • Exomes 𝑓: 0.29 (25496 hom. 73498 hem.)
• Consequence: ANOS1 NM_000216.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.186
• Publications: 4 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-8533079-C-A is Benign according to our data. Variant chrX-8533079-C-A is described in ClinVar as Benign. ClinVar VariationId is 1236328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 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.1985-26G>T		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.1985-26G>T		intron	N/A	ENSP00000262648.3	P23352
	ANOS1	ENST00000921740.1		c.1982-26G>T		intron	N/A	ENSP00000591799.1
	ANOS1	ENST00000921741.1		c.1838-26G>T		intron	N/A	ENSP00000591800.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 33808 AN: 111112 Hom.: 3873 Cov.: 23

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.289

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.303

GnomAD2 exomes AF: 0.298 AC: 51473 AN: 172643 AF XY: 0.303

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.339

Gnomad EAS exome AF: 0.579

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.289 AC: 243402 AN: 841857 Hom.: 25496 Cov.: 15 AF XY: 0.313 AC XY: 73498 AN XY: 234725

African (AFR) AF: 0.331 AC: 7164 AN: 21640

American (AMR) AF: 0.149 AC: 5152 AN: 34615

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 5928 AN: 17683

East Asian (EAS) AF: 0.550 AC: 15922 AN: 28927

South Asian (SAS) AF: 0.318 AC: 15421 AN: 48456

European-Finnish (FIN) AF: 0.302 AC: 12061 AN: 39913

Middle Eastern (MID) AF: 0.325 AC: 1165 AN: 3588

European-Non Finnish (NFE) AF: 0.278 AC: 169193 AN: 609658

Other (OTH) AF: 0.305 AC: 11396 AN: 37377

GnomAD4 genome AF: 0.304 AC: 33824 AN: 111164 Hom.: 3873 Cov.: 23 AF XY: 0.295 AC XY: 9871 AN XY: 33406

African (AFR) AF: 0.327 AC: 9984 AN: 30572

American (AMR) AF: 0.207 AC: 2181 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 880 AN: 2637

East Asian (EAS) AF: 0.573 AC: 1992 AN: 3478

South Asian (SAS) AF: 0.289 AC: 770 AN: 2668

European-Finnish (FIN) AF: 0.310 AC: 1835 AN: 5913

Middle Eastern (MID) AF: 0.294 AC: 63 AN: 214

European-Non Finnish (NFE) AF: 0.292 AC: 15434 AN: 52937

Other (OTH) AF: 0.306 AC: 463 AN: 1511

Alfa AF: 0.319 Hom.: 3042

Bravo AF: 0.301

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.70
DANN	Benign	0.44
PhyloP100		-0.19
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41303179; hg19: chrX-8501120; COSMIC: COSV52924123; COSMIC: COSV52924123;