NM_000216.4:c.1A>T

Variant names:

• chrX-8732036-T-A
• rs606231409
• NM_000216.4:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000216.4(ANOS1):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ANOS1 NM_000216.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.47
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 46 pathogenic variants. Next in-frame start position is after 335 codons. Genomic position: 8570558. Lost 0.491 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-8732036-T-A is Pathogenic according to our data. Variant chrX-8732036-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 463527.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	NP_000207.2	P23352
	ANOS1	NM_001440775.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 9	NP_001427704.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANOS1	ENST00000262648.8	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000262648.3	P23352
	ANOS1	ENST00000921740.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000591799.1
	ANOS1	ENST00000921741.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 13	ENSP00000591800.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypogonadotropic hypogonadism 1 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.31	T
PhyloP100		3.5
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.52	P
Vest4		0.88
MutPred		1.0		Loss of helix (P = 0.2022)
MVP		0.99
ClinPred		0.73	D
GERP RS		3.0
PromoterAI		-0.37	Neutral
Varity_R		0.93
gMVP		0.57
Mutation Taster		=19/181	disease causing (ClinVar)

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: rs606231409; hg19: chrX-8700077;