dbSNP rs150996735: AFF2:p.Pro166Ser (chrX-148662223-C-T) – 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.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. 16/21 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

Publications

7 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, Labcorp Genetics (formerly Invitae), G2P
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=0.0071786046).

BP6

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

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 23 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	UniProt
AFF2	NM_002025.4	MANE Select	c.496C>T	p.Pro166Ser	missense	Exon 3 of 21	NP_002016.2	P51816-1
AFF2	NM_001169123.2		c.484C>T	p.Pro162Ser	missense	Exon 3 of 21	NP_001162594.1	P51816-5
AFF2	NM_001169122.2		c.484C>T	p.Pro162Ser	missense	Exon 3 of 20	NP_001162593.1	P51816-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AFF2	ENST00000370460.7	TSL:5 MANE Select	c.496C>T	p.Pro166Ser	missense	Exon 3 of 21	ENSP00000359489.2	P51816-1
AFF2	ENST00000342251.7	TSL:1	c.484C>T	p.Pro162Ser	missense	Exon 3 of 20	ENSP00000345459.4	P51816-3
AFF2	ENST00000370457.9	TSL:1	c.496C>T	p.Pro166Ser	missense	Exon 3 of 20	ENSP00000359486.6	P51816-6

Frequencies

GnomAD3 genomes

AF:

0.000897

AC:

100

AN:

111514

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000889

AC:

163

AN:

183392

AF XY:

0.000929

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 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

African (AFR)

AF:

0.000114

AC:

AN:

26393

American (AMR)

AF:

0.000795

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00129

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.000591

AC:

AN:

54134

European-Finnish (FIN)

AF:

0.0000987

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.000726

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00161

AC:

1351

AN:

841682

Other (OTH)

AF:

0.00122

AC:

AN:

46082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000896

AC:

100

AN:

111566

Hom.:

Cov.:

AF XY:

0.000681

AC XY:

AN XY:

33796

show subpopulations

African (AFR)

AF:

0.000195

AC:

AN:

30700

American (AMR)

AF:

0.000285

AC:

AN:

10513

Ashkenazi Jewish (ASJ)

AF:

0.00114

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6037

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00164

AC:

AN:

53101

Other (OTH)

AF:

0.000663

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

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:

0.000945

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.24

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.12

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.66

M_CAP

Benign

0.030

MetaRNN

Benign

0.0072

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.40

PhyloP100

-0.20

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.86

REVEL

Benign

0.084

Sift

Benign

0.36

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.033

MVP

0.17

MPC

0.14

ClinPred

0.023

GERP RS

-6.0

Varity_R

0.037

gMVP

0.33

Mutation Taster

=97/3

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

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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