X-148652065-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002025.4(AFF2):c.114G>T(p.Gln38His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,088,424 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFF2	NM_002025.4	c.114G>T	p.Gln38His	missense_variant	2/21	ENST00000370460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFF2	ENST00000370460.7	c.114G>T	p.Gln38His	missense_variant	2/21	5	NM_002025.4	P1
AFF2	ENST00000342251.7	c.114G>T	p.Gln38His	missense_variant	2/20	1
AFF2	ENST00000370457.9	c.114G>T	p.Gln38His	missense_variant	2/20	1
AFF2	ENST00000370458.5	c.114G>T	p.Gln38His	missense_variant	2/8	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1088424 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 354206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The c.114G>T (p.Q38H) alteration is located in exon 2 (coding exon 2) of the AFF2 gene. This alteration results from a G to T substitution at nucleotide position 114, causing the glutamine (Q) at amino acid position 38 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.2	L;L;L;L
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.11	T;D;T;D
Sift4G	Benign	0.28	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.47
MutPred		0.72		Loss of disorder (P = 0.152);Loss of disorder (P = 0.152);Loss of disorder (P = 0.152);Loss of disorder (P = 0.152);
MVP		0.72
MPC		0.59
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.54
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-147733586;