chrX-8533023-T-C

Position:

• chrX-8533023-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000216.4(ANOS1):​c.2015A>G​(p.His672Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,170,607 control chromosomes in the GnomAD database, including 1 homozygotes. There are 112 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 16 hem., cov: 22)
  • Exomes 𝑓: 0.00027 (1 hom. 96 hem.)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.16

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1433368).
• BP6: Variant X-8533023-T-C is Benign according to our data. Variant chrX-8533023-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224350.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0004 (45/112406) while in subpopulation NFE AF= 0.000675 (36/53311). AF 95% confidence interval is 0.000501. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 16 XL,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANOS1	NM_000216.4	c.2015A>G	p.His672Arg	missense_variant	14/14	ENST00000262648.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.2015A>G	p.His672Arg	missense_variant	14/14	1	NM_000216.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 45 AN: 112356 Hom.: 0 Cov.: 22 AF XY: 0.000464 AC XY: 16 AN XY: 34506

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.000326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000675

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000280 AC: 51 AN: 181953 Hom.: 0 AF XY: 0.000255 AC XY: 17 AN XY: 66615

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000266

Gnomad FIN exome AF: 0.0000629

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000275 AC: 291 AN: 1058201 Hom.: 1 Cov.: 23 AF XY: 0.000290 AC XY: 96 AN XY: 331339

Gnomad4 AFR exome AF: 0.0000390

Gnomad4 AMR exome AF: 0.000171

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000245

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000324

Gnomad4 OTH exome AF: 0.000179

GnomAD4 genome AF: 0.000400 AC: 45 AN: 112406 Hom.: 0 Cov.: 22 AF XY: 0.000463 AC XY: 16 AN XY: 34566

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.000326

Gnomad4 NFE AF: 0.000675

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000649 Hom.: 5

Bravo AF: 0.000321

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	- -
Uncertain significance, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -

Amenorrhea Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 08, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.82	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Benign	0.058	T
Sift4G	Uncertain	0.019	D
Polyphen		0.95	P
Vest4		0.15
MVP		0.59
MPC		0.56
ClinPred		0.17	T
GERP RS		3.8
Varity_R		0.43
gMVP		0.37

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: rs199771303; hg19: chrX-8501064;