rs150996735

Positions:

chrX-148662223-C-T

Variant summary

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

The NM_002025.4(AFF2):c.496C>T(p.Pro166Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,209,320 control chromosomes in the GnomAD database, including 4 homozygotes. There are 519 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 0.00090 ( 1 hom., 23 hem., cov: 23)

Exomes 𝑓: 0.0014 ( 3 hom. 496 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.195

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=0.0071786046).

BP6

Variant X-148662223-C-T is Benign according to our data. Variant chrX-148662223-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-148662223-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000896 (100/111566) while in subpopulation NFE AF= 0.00164 (87/53101). AF 95% confidence interval is 0.00136. There are 1 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF2	NM_002025.4 linkuse as main transcript	c.496C>T	p.Pro166Ser	missense_variant	3/21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AFF2	ENST00000370460.7 linkuse as main transcript	c.496C>T	p.Pro166Ser	missense_variant	3/21	5	NM_002025.4	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7 linkuse as main transcript	c.484C>T	p.Pro162Ser	missense_variant	3/20	1		ENSP00000345459.4	P51816-3
AFF2	ENST00000370457.9 linkuse as main transcript	c.496C>T	p.Pro166Ser	missense_variant	3/20	1		ENSP00000359486.6	P51816-6
AFF2	ENST00000370458.5 linkuse as main transcript	c.484C>T	p.Pro162Ser	missense_variant	3/8	1		ENSP00000359487.1	P51816-4

Frequencies

GnomAD3 genomes

AF:

0.000897

AC:

100

AN:

111514

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

AN XY:

33734

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

Gnomad ASJ

AF:

0.00114

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00164

Gnomad OTH

AF:

0.000671

GnomAD3 exomes

AF:

0.000889

AC:

163

AN:

183392

Hom.:

AF XY:

0.000929

AC XY:

AN XY:

67840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000802

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.000883

GnomAD4 exome

AF:

0.00137

AC:

1502

AN:

1097754

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

496

AN XY:

363110

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000795

Gnomad4 ASJ exome

AF:

0.00129

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.0000987

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00122

GnomAD4 genome

AF:

0.000896

AC:

100

AN:

111566

Hom.:

Cov.:

AF XY:

0.000681

AC XY:

AN XY:

33796

show subpopulations

Gnomad4 AFR

AF:

0.000195

Gnomad4 AMR

AF:

0.000285

Gnomad4 ASJ

AF:

0.00114

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00164

Gnomad4 OTH

AF:

0.000663

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.000945

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000840

AC:

102

EpiCase

AF:

0.00153

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.24

DANN

Benign

0.40

DEOGEN2

Benign

0.12

T;.;.;.

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.66

T;T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.0072

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.40

N;.;.;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.86

N;N;N;.

REVEL

Benign

0.084

Sift

Benign

0.36

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.033

MVP

0.17

MPC

0.14

ClinPred

0.023

GERP RS

-6.0

Varity_R

0.037

gMVP

0.33

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