NM_004529.4:c.1125+2365C>T

Variant names:

• chr9-20411356-G-A
• rs16938058
• NM_004529.4:c.1125+2365C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004529.4(MLLT3):​c.1125+2365C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0863 in 152,916 control chromosomes in the GnomAD database, including 1,215 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 0.087 (1214 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1 hom.)
• Consequence: MLLT3 NM_004529.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.670

Genes affected

MLLT3 (HGNC:7136): (MLLT3 super elongation complex subunit) Enables chromatin binding activity and lysine-acetylated histone binding activity. Involved in several processes, including hematopoietic stem cell differentiation; positive regulation of transcription, DNA-templated; and regulation of stem cell division. Acts upstream of or within negative regulation of canonical Wnt signaling pathway and positive regulation of Wnt signaling pathway, planar cell polarity pathway. Located in cytosol and nucleoplasm. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

MIR4473 (HGNC:41540): (microRNA 4473) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLLT3	NM_004529.4	c.1125+2365C>T		intron_variant	Intron 5 of 10	ENST00000380338.9	NP_004520.2
MLLT3	NM_001286691.2	c.1116+2365C>T		intron_variant	Intron 5 of 10		NP_001273620.1
MIR4473	NR_039684.1	n.-118C>T		upstream_gene_variant
MIR4473	unassigned_transcript_1582	n.-174C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLLT3	ENST00000380338.9	c.1125+2365C>T		intron_variant	Intron 5 of 10	1	NM_004529.4	ENSP00000369695.4

Frequencies

GnomAD3 genomes AF: 0.0864 AC: 13144 AN: 152060 Hom.: 1207 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0421

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0774

GnomAD4 exome AF: 0.0379 AC: 28 AN: 738 Hom.: 1 AF XY: 0.0378 AC XY: 14 AN XY: 370

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.0667

Gnomad4 NFE exome AF: 0.0181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0866 AC: 13173 AN: 152178 Hom.: 1214 Cov.: 32 AF XY: 0.0878 AC XY: 6534 AN XY: 74418

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.0934

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.0421

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.0766

Alfa AF: 0.0312 Hom.: 297

Bravo AF: 0.100

Asia WGS AF: 0.102 AC: 355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs16938058; hg19: chr9-20411354;