rs142559324

Positions:

chrX-148662220-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002025.4(AFF2):c.493A>G(p.Asn165Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000951 in 1,209,731 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.000073 ( 0 hom. 23 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.41

Variant links:

Genes affected

AFF2 (HGNC:3776): (ALF transcription elongation factor 2) This gene encodes a putative transcriptional activator that is a member of the AF4\FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked cognitive disability. In addition, this gene contains 6-25 GCC repeats that are expanded to >200 repeats in the disease state. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jul 2016]

AFF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003784418).

BP6

Variant X-148662220-A-G is Benign according to our data. Variant chrX-148662220-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-148662220-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000313 (35/111800) while in subpopulation EAS AF= 0.00451 (16/3544). AF 95% confidence interval is 0.00283. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF2	NM_002025.4 linkuse as main transcript	c.493A>G	p.Asn165Asp	missense_variant	3/21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7 linkuse as main transcript	c.493A>G	p.Asn165Asp	missense_variant	3/21	5	NM_002025.4	ENSP00000359489	P1	P51816-1
AFF2	ENST00000342251.7 linkuse as main transcript	c.481A>G	p.Asn161Asp	missense_variant	3/20	1		ENSP00000345459		P51816-3
AFF2	ENST00000370457.9 linkuse as main transcript	c.493A>G	p.Asn165Asp	missense_variant	3/20	1		ENSP00000359486		P51816-6
AFF2	ENST00000370458.5 linkuse as main transcript	c.481A>G	p.Asn161Asp	missense_variant	3/8	1		ENSP00000359487		P51816-4

Frequencies

GnomAD3 genomes

AF:

0.000304

AC:

AN:

111748

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

33912

show subpopulations

Gnomad AFR

AF:

0.000554

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00450

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

183398

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

67846

show subpopulations

Gnomad AFR exome

AF:

0.000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00260

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.0000729

AC:

AN:

1097931

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363285

show subpopulations

Gnomad4 AFR exome

AF:

0.000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00139

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000651

GnomAD4 genome

AF:

0.000313

AC:

AN:

111800

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

AN XY:

33974

show subpopulations

Gnomad4 AFR

AF:

0.000552

Gnomad4 AMR

AF:

0.0000950

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00451

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000663

Alfa

AF:

0.0000669

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000313

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.23

T;.;.;.

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.72

T;T;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.0

N;N;N;.

REVEL

Benign

0.13

Sift

Benign

0.60

T;T;T;.

Sift4G

Benign

0.66

T;T;T;T

Polyphen

0.52

P;B;B;B

Vest4

0.15

MVP

0.83

MPC

0.21

ClinPred

0.017

GERP RS

4.4

Varity_R

0.16

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over