rs1437377

Variant names:

• chr2-100128462-T-G
• rs1437377
• NM_001386135.1:c.-145+762A>C

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+762A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,108 control chromosomes in the GnomAD database, including 4,583 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 0.21 (4583 hom., cov: 32)
• Consequence: AFF3 NM_001386135.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 10 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=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 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+762A>C		intron	N/A	NP_001373064.1	P51826-1
	AFF3	NM_002285.3		c.-145+14022A>C		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+762A>C		intron	N/A	ENSP00000500419.1	P51826-1
	AFF3	ENST00000317233.8	TSL:5	c.-145+14022A>C		intron	N/A	ENSP00000317421.4	P51826-1
	AFF3	ENST00000672204.1		c.-145+14022A>C		intron	N/A	ENSP00000500616.1	A0A5F9ZHV2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31329 AN: 151990 Hom.: 4570 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0767

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.193

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

GnomAD4 genome AF: 0.206 AC: 31384 AN: 152108 Hom.: 4583 Cov.: 32 AF XY: 0.200 AC XY: 14848 AN XY: 74350

African (AFR) AF: 0.412 AC: 17086 AN: 41462

American (AMR) AF: 0.123 AC: 1876 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 694 AN: 3468

East Asian (EAS) AF: 0.0769 AC: 397 AN: 5162

South Asian (SAS) AF: 0.179 AC: 864 AN: 4820

European-Finnish (FIN) AF: 0.0649 AC: 688 AN: 10606

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9043 AN: 67994

Other (OTH) AF: 0.192 AC: 405 AN: 2114

Alfa AF: 0.157 Hom.: 1209

Bravo AF: 0.217

Asia WGS AF: 0.147 AC: 513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		1.2
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: rs1437377; hg19: chr2-100744924; COSMIC: COSV57847490;