rs1057518785

Variant names:

• chrX-148967634-A-G
• rs1057518785
• NM_002025.4:c.3209A>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, multiple submitters, no conflicts U:2
• 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 rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.3209A>G	p.His1070Arg	missense_variant	Exon 15 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.3209A>G	p.His1070Arg	missense_variant	Exon 15 of 21	5	NM_002025.4	ENSP00000359489.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3209A>G (p.H1070R) alteration is located in exon 15 (coding exon 15) of the AFF2 gene. This alteration results from a A to G substitution at nucleotide position 3209, causing the histidine (H) at amino acid position 1070 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Mar 31, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.;.
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;