9-20414151-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004529.4(MLLT3):c.695C>T(p.Ser232Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLLT3 NM_004529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.311906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLLT3	NM_004529.4	c.695C>T	p.Ser232Phe	missense_variant	5/11	ENST00000380338.9
MLLT3	NM_001286691.2	c.686C>T	p.Ser229Phe	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLLT3	ENST00000380338.9	c.695C>T	p.Ser232Phe	missense_variant	5/11	1	NM_004529.4	P4
MLLT3	ENST00000630269.2	c.686C>T	p.Ser229Phe	missense_variant	5/11	2		A1
MLLT3	ENST00000475957.1	n.652C>T		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.695C>T (p.S232F) alteration is located in exon 5 (coding exon 5) of the MLLT3 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the serine (S) at amino acid position 232 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.056	T;T
Polyphen		0.99	D;.
Vest4		0.49
MutPred		0.24		Loss of phosphorylation at S232 (P = 8e-04);.;
MVP		0.28
MPC		0.17
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.26
gMVP		0.17

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: rs1822802961; hg19: chr9-20414149; COSMIC: COSV63498029; COSMIC: COSV63498029;