rs140927355

chrX-148962804-G-AchrX-148962804-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.61

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 194202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-148962804-G-A is described in Lovd as [Benign]. Variant chrX-148962804-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.2780G>A	p.Arg927His	missense_variant	13/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.2780G>A	p.Arg927His	missense_variant	13/21	5	NM_002025.4	P1

Frequencies

GnomAD3 genomes AF: 0.000804 AC: 90 AN: 111939 Hom.: 0 Cov.: 23 AF XY: 0.000850 AC XY: 29 AN XY: 34125

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

GnomAD3 exomes AF: 0.00170 AC: 311 AN: 183174 Hom.: 0 AF XY: 0.00197 AC XY: 133 AN XY: 67672

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 SAS exome AF: 0.00488

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.: 2 Cov.: 30 AF XY: 0.00125 AC XY: 453 AN XY: 361702

Gnomad4 AFR exome AF: 0.000417

Gnomad4 AMR exome AF: 0.000568

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00544

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000447

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.000804 AC: 90 AN: 111989 Hom.: 0 Cov.: 23 AF XY: 0.000848 AC XY: 29 AN XY: 34185

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.000285

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00340

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000564

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00137 Hom.: 51

Bravo AF: 0.000861

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.00165 AC: 200

EpiCase AF: 0.000927

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 21, 2016	- -

FRAXE Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AFF2: BP4, BS2 -

AFF2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.13	N;N;.;N
REVEL	Benign	0.29
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Benign	0.23	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.059
MVP		0.93
MPC		0.65
ClinPred		0.042	T
GERP RS		5.9
Varity_R		0.19
gMVP		0.32

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

Other links and lift over

dbSNP: rs140927355; hg19: chrX-148044334; COSMIC: COSV54000778;