rs1057518785

Positions:

• chrX-148967634-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002025.4(AFF2):​c.3209A>G​(p.His1070Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.11

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37604493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.3209A>G	p.His1070Arg	missense_variant	15/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.3209A>G	p.His1070Arg	missense_variant	15/21	5	NM_002025.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hirsutism;C0026351:Intellectual disability, moderate;C0026827:Hypotonia;C0027092:Myopia;C0349588:Short stature;C0431447:Synophrys;C2677180:Primary microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 31, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.38	T;.;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.89	P;B;B;.
Vest4		0.34
MutPred		0.48		Gain of MoRF binding (P = 0.0491);.;.;.;
MVP		0.92
MPC		1.3
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.54

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: rs1057518785; hg19: chrX-148049164;