2-99659904-G-A

Variant names:

• chr2-99659904-G-A
• rs10496338
• NM_001386135.1:c.1144-10238C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386135.1(AFF3):​c.1144-10238C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 152,240 control chromosomes in the GnomAD database, including 162 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 0.014 (162 hom., cov: 33)
• Consequence: AFF3 NM_001386135.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.251
• Publications: 0 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

ENSG00000301580 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFF3	NM_001386135.1	c.1144-10238C>T		intron_variant	Intron 12 of 24	ENST00000672756.2	NP_001373064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFF3	ENST00000672756.2	c.1144-10238C>T		intron_variant	Intron 12 of 24		NM_001386135.1	ENSP00000500419.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2044 AN: 152122 Hom.: 155 Cov.: 33

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.0158

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

GnomAD4 genome AF: 0.0136 AC: 2063 AN: 152240 Hom.: 162 Cov.: 33 AF XY: 0.0144 AC XY: 1072 AN XY: 74428

African (AFR) AF: 0.00330 AC: 137 AN: 41554

American (AMR) AF: 0.111 AC: 1693 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00250 AC: 170 AN: 68014

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.00796 Hom.: 18

Bravo AF: 0.0245

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.79
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs10496338; hg19: chr2-100276366;