Genetic Variant NM_002025.4:c.2780G>A (chrX-148962804-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002025.4(AFF2):c.2780G>A(p.Arg927His) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,208,209 control chromosomes in the GnomAD database, including 2 homozygotes. There are 482 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., 29 hem., cov: 23)

Exomes 𝑓: 0.0010 ( 2 hom. 453 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.61

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

FRAXE intellectual disability
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

AFF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070457757).

BP6

Variant X-148962804-G-A is Benign according to our data. Variant chrX-148962804-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000804 (90/111989) while in subpopulation SAS AF = 0.0034 (9/2649). AF 95% confidence interval is 0.00177. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 29 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AFF2	NM_002025.4	MANE Select	c.2780G>A	p.Arg927His	missense	Exon 13 of 21	NP_002016.2
AFF2	NM_001169123.2		c.2750G>A	p.Arg917His	missense	Exon 13 of 21	NP_001162594.1
AFF2	NM_001169122.2		c.2681G>A	p.Arg894His	missense	Exon 12 of 20	NP_001162593.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AFF2	ENST00000370460.7	TSL:5 MANE Select	c.2780G>A	p.Arg927His	missense	Exon 13 of 21	ENSP00000359489.2
AFF2	ENST00000342251.7	TSL:1	c.2681G>A	p.Arg894His	missense	Exon 12 of 20	ENSP00000345459.4
AFF2	ENST00000370457.9	TSL:1	c.2675G>A	p.Arg892His	missense	Exon 12 of 20	ENSP00000359486.6

Frequencies

GnomAD3 genomes

AF:

0.000804

AC:

AN:

111939

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00339

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000564

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.00170

AC:

311

AN:

183174

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000475

Gnomad ASJ exome

AF:

0.0169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000758

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00103

AC:

1126

AN:

1096220

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

453

AN XY:

361702

show subpopulations

African (AFR)

AF:

0.000417

AC:

AN:

26353

American (AMR)

AF:

0.000568

AC:

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

331

AN:

19370

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30187

South Asian (SAS)

AF:

0.00544

AC:

294

AN:

54060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00218

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.000447

AC:

376

AN:

840370

Other (OTH)

AF:

0.00182

AC:

AN:

46034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000804

AC:

AN:

111989

Hom.:

Cov.:

AF XY:

0.000848

AC XY:

AN XY:

34185

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30830

American (AMR)

AF:

0.000285

AC:

AN:

10538

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00340

AC:

AN:

2649

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000564

AC:

AN:

53218

Other (OTH)

AF:

0.00131

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000861

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.00165

AC:

200

EpiCase

AF:

0.000927

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

FRAXE (2)

not specified (2)

AFF2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.0070

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.1

PhyloP100

3.6

PrimateAI

Benign

0.42

PROVEAN

Benign

0.13

REVEL

Benign

0.29

Sift

Uncertain

0.0030

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.059

MVP

0.93

MPC

0.65

ClinPred

0.042

GERP RS

5.9

Varity_R

0.19

gMVP

0.32

Mutation Taster

=78/22

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over