2-100123508-T-C

Variant names:

• chr2-100123508-T-C
• rs6706188
• NM_001386135.1:c.-145+5716A>G

Variant summary

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

The NM_001386135.1(AFF3):​c.-145+5716A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 152,082 control chromosomes in the GnomAD database, including 12,474 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 0.36 (12474 hom., cov: 32)
• Consequence: AFF3 NM_001386135.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 15 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386135.1. 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
	AFF3	NM_001386135.1	MANE Select	c.-145+5716A>G		intron	N/A	NP_001373064.1	P51826-1
	AFF3	NM_002285.3		c.-144-17925A>G		intron	N/A	NP_002276.2	P51826-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFF3	ENST00000672756.2	MANE Select	c.-145+5716A>G		intron	N/A	ENSP00000500419.1	P51826-1
	AFF3	ENST00000317233.8	TSL:5	c.-144-17925A>G		intron	N/A	ENSP00000317421.4	P51826-1
	AFF3	ENST00000672204.1		c.-144-17925A>G		intron	N/A	ENSP00000500616.1	A0A5F9ZHV2

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55081 AN: 151964 Hom.: 12442 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.0778

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.309

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

GnomAD4 genome AF: 0.363 AC: 55151 AN: 152082 Hom.: 12474 Cov.: 32 AF XY: 0.354 AC XY: 26345 AN XY: 74332

African (AFR) AF: 0.642 AC: 26610 AN: 41446

American (AMR) AF: 0.201 AC: 3077 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 872 AN: 3464

East Asian (EAS) AF: 0.0780 AC: 404 AN: 5182

South Asian (SAS) AF: 0.274 AC: 1318 AN: 4816

European-Finnish (FIN) AF: 0.270 AC: 2851 AN: 10566

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19008 AN: 67998

Other (OTH) AF: 0.306 AC: 647 AN: 2114

Alfa AF: 0.299 Hom.: 23998

Bravo AF: 0.365

Asia WGS AF: 0.206 AC: 719 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.37
DANN	Benign	0.36
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6706188; hg19: chr2-100739970;