Variant chrX-148955685-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002025.4(AFF2):c.1640G>A(p.Gly547Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,209,656 control chromosomes in the GnomAD database, including 2 homozygotes. There are 51 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.00014 ( 2 hom. 50 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.39

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=0.011382073).

BP6

Variant X-148955685-G-A is Benign according to our data. Variant chrX-148955685-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000626 (7/111748) while in subpopulation EAS AF= 0.00197 (7/3553). AF 95% confidence interval is 0.000924. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4 linkuse as main transcript	c.1640G>A	p.Gly547Asp	missense_variant	11/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7 linkuse as main transcript	c.1640G>A	p.Gly547Asp	missense_variant	11/21	5	NM_002025.4	P1	P51816-1

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

111695

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33875

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00196

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:

0.000268

AC:

AN:

182952

Hom.:

AF XY:

0.000297

AC XY:

AN XY:

67410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00354

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000143

AC:

157

AN:

1097908

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

363264

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00513

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000626

AC:

AN:

111748

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33938

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000313

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	AFF2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;.;.

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.63

N;N;.;N

REVEL

Benign

0.15

Sift

Benign

0.52

T;T;.;T

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.90

P;P;P;.

Vest4

0.69

MutPred

0.48

Gain of ubiquitination at K542 (P = 0.0558);.;.;.;

MVP

0.78

MPC

0.64

ClinPred

0.085

GERP RS

4.3

Varity_R

0.18

gMVP

0.082

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