X-8534420-G-A

Position:

• chrX-8534420-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000216.4(ANOS1):​c.1883C>T​(p.Thr628Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,954 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: ANOS1 NM_000216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANOS1	NM_000216.4	c.1883C>T	p.Thr628Ile	missense_variant	13/14	ENST00000262648.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANOS1	ENST00000262648.8	c.1883C>T	p.Thr628Ile	missense_variant	13/14	1	NM_000216.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096954 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2017

The T628I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T628I is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.51	N
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.046	D
Sift4G	Uncertain	0.020	D
Polyphen		0.27	B
Vest4		0.32
MutPred		0.75		Loss of disorder (P = 0.0927);
MVP		0.34
MPC		0.33
ClinPred		0.75	D
GERP RS		4.2
Varity_R		0.11
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1064796699; hg19: chrX-8502461;