chr9-20411356-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004529.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLLT3	NM_004529.4	MANE Select	c.1125+2365C>T		intron	N/A	NP_004520.2
	MLLT3	NM_001286691.2		c.1116+2365C>T		intron	N/A	NP_001273620.1
	MIR4473	NR_039684.1		n.-118C>T		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLLT3	ENST00000380338.9	TSL:1 MANE Select	c.1125+2365C>T		intron	N/A	ENSP00000369695.4
	MLLT3	ENST00000630269.2	TSL:2	c.1116+2365C>T		intron	N/A	ENSP00000485996.1
	MLLT3	ENST00000468513.5	TSL:3	n.147+460C>T		intron	N/A

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

African (AFR) AF: 0.250 AC: 5 AN: 20

American (AMR) AF: 0.500 AC: 2 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.0667 AC: 2 AN: 30

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.0339 AC: 16 AN: 472

European-Non Finnish (NFE) AF: 0.0181 AC: 3 AN: 166

Other (OTH) AF: 0.00 AC: 0 AN: 42

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

African (AFR) AF: 0.223 AC: 9232 AN: 41488

American (AMR) AF: 0.0934 AC: 1429 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.191 AC: 991 AN: 5178

South Asian (SAS) AF: 0.0421 AC: 203 AN: 4822

European-Finnish (FIN) AF: 0.0240 AC: 255 AN: 10606

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 882 AN: 68014

Other (OTH) AF: 0.0766 AC: 161 AN: 2102

Alfa AF: 0.0397 Hom.: 538

Bravo AF: 0.100

Asia WGS AF: 0.102 AC: 355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.67
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: rs16938058; hg19: chr9-20411354; COSMIC: COSV107453710; COSMIC: COSV107453710;