2-99647995-G-T

Variant names:

• chr2-99647995-G-T
• rs10514778
• NM_001386135.1:c.1184+1631C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001386135.1(AFF3):​c.1184+1631C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 152,222 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.034 (106 hom., cov: 33)
• Consequence: AFF3 NM_001386135.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.366
• Publications: 2 publications found

Genes affected

AFF3 (HGNC:6473): (ALF transcription elongation factor 3) This gene encodes a tissue-restricted nuclear transcriptional activator that is preferentially expressed in lymphoid tissue. Isolation of this protein initially defined a highly conserved LAF4/MLLT2 gene family of nuclear transcription factors that may function in lymphoid development and oncogenesis. In some ALL patients, this gene has been found fused to the gene for MLL. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

AFF3 Gene-Disease associations (from GenCC):

• KINSSHIP syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0338 (5152/152222) while in subpopulation NFE AF = 0.0433 (2944/67998). AF 95% confidence interval is 0.042. There are 106 homozygotes in GnomAd4. There are 2489 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF3	NM_001386135.1	c.1184+1631C>A		intron_variant	Intron 13 of 24	ENST00000672756.2	NP_001373064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF3	ENST00000672756.2	c.1184+1631C>A		intron_variant	Intron 13 of 24		NM_001386135.1	ENSP00000500419.1

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5149 AN: 152104 Hom.: 106 Cov.: 33

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0307

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0338 AC: 5152 AN: 152222 Hom.: 106 Cov.: 33 AF XY: 0.0334 AC XY: 2489 AN XY: 74416

African (AFR) AF: 0.0221 AC: 919 AN: 41542

American (AMR) AF: 0.0328 AC: 501 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.0352 AC: 183 AN: 5192

South Asian (SAS) AF: 0.00893 AC: 43 AN: 4816

European-Finnish (FIN) AF: 0.0390 AC: 413 AN: 10594

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2944 AN: 67998

Other (OTH) AF: 0.0303 AC: 64 AN: 2110

Alfa AF: 0.0140 Hom.: 6

Bravo AF: 0.0336

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.39
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs10514778; hg19: chr2-100264457;