X-148501123-A-G

Variant names:

• chrX-148501123-A-G
• NM_002025.4:c.26A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002025.4(AFF2):​c.26A>G​(p.Asp9Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: AFF2 NM_002025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.43

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.26A>G	p.Asp9Gly	missense_variant	Exon 1 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.26A>G	p.Asp9Gly	missense_variant	Exon 1 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000342251.7	c.26A>G	p.Asp9Gly	missense_variant	Exon 1 of 20	1		ENSP00000345459.4
AFF2	ENST00000370457.9	c.26A>G	p.Asp9Gly	missense_variant	Exon 1 of 20	1		ENSP00000359486.6
AFF2	ENST00000370458.5	c.26A>G	p.Asp9Gly	missense_variant	Exon 1 of 8	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097184 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 362774

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.69	N;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.74	N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		0.96	P;D;D;D
Vest4		0.36
MutPred		0.28		Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);
MVP		0.77
MPC		0.19
ClinPred		0.69	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.52

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-147582643;