NM_002025.4:c.178T>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 14/23 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y60C) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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]

AFF2 Gene-Disease associations (from GenCC):

• FRAXE intellectual disability

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	NM_002025.4	MANE Select	c.178T>C	p.Tyr60His	missense splice_region	Exon 2 of 21	NP_002016.2	P51816-1
	AFF2	NM_001169124.2		c.178T>C	p.Tyr60His	missense splice_region	Exon 2 of 20	NP_001162595.1	P51816-6
	AFF2	NM_001169123.2		c.168+10T>C		intron	N/A	NP_001162594.1	P51816-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF2	ENST00000370460.7	TSL:5 MANE Select	c.178T>C	p.Tyr60His	missense splice_region	Exon 2 of 21	ENSP00000359489.2	P51816-1
	AFF2	ENST00000370457.9	TSL:1	c.178T>C	p.Tyr60His	missense splice_region	Exon 2 of 20	ENSP00000359486.6	P51816-6
	AFF2	ENST00000342251.7	TSL:1	c.168+10T>C		intron	N/A	ENSP00000345459.4	P51816-3

Frequencies

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

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

African (AFR) AF: 0.00 AC: 0 AN: 25537

American (AMR) AF: 0.00 AC: 0 AN: 32559

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18690

East Asian (EAS) AF: 0.00 AC: 0 AN: 30051

South Asian (SAS) AF: 0.00 AC: 0 AN: 51386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40365

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4033

European-Non Finnish (NFE) AF: 0.0000181 AC: 15 AN: 826471

Other (OTH) AF: 0.00 AC: 0 AN: 45185

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30784

American (AMR) AF: 0.00 AC: 0 AN: 10519

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53166

Other (OTH) AF: 0.00 AC: 0 AN: 1507

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.25	T
Polyphen		0.93	P
Vest4		0.16
MutPred		0.51		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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1298554052; hg19: chrX-147733650;