chrX-148652129-T-C

Variant names:

• chrX-148652129-T-C
• rs1298554052
• NM_002025.4:c.178T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002025.4(AFF2):​c.178T>C​(p.Tyr60His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,186,144 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom. 6 hem.)
• Consequence: AFF2 NM_002025.4 missense, splice_region
• Scores: Splicing: ADA: 0.003907
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.65

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20219377).
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF2	NM_002025.4	c.178T>C	p.Tyr60His	missense_variant, splice_region_variant	Exon 2 of 21	ENST00000370460.7	NP_002016.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7	c.178T>C	p.Tyr60His	missense_variant, splice_region_variant	Exon 2 of 21	5	NM_002025.4	ENSP00000359489.2
AFF2	ENST00000370457.9	c.178T>C	p.Tyr60His	missense_variant, splice_region_variant	Exon 2 of 20	1		ENSP00000359486.6
AFF2	ENST00000342251.7	c.168+10T>C		intron_variant	Intron 2 of 19	1		ENSP00000345459.4
AFF2	ENST00000370458.5	c.168+10T>C		intron_variant	Intron 2 of 7	1		ENSP00000359487.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111867 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34035

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000140 AC: 15 AN: 1074277 Hom.: 0 Cov.: 25 AF XY: 0.0000175 AC XY: 6 AN XY: 343123

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: 0.0000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111867 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34035

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:3

Aug 07, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.22	N;.
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.25	T;T
Polyphen		0.93	P;P
Vest4		0.16
MutPred		0.51		Gain of disorder (P = 0.0433);Gain of disorder (P = 0.0433);
MVP		0.46
MPC		0.67
ClinPred		0.64	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.090
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: rs1298554052; hg19: chrX-147733650;