9-20354815-C-T

Variant names:

• chr9-20354815-C-T
• NM_004529.4:c.1496G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004529.4(MLLT3):​c.1496G>A​(p.Cys499Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.76

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]

LOC124902129 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLLT3	NM_004529.4	c.1496G>A	p.Cys499Tyr	missense_variant	Exon 9 of 11	ENST00000380338.9	NP_004520.2
MLLT3	NM_001286691.2	c.1487G>A	p.Cys496Tyr	missense_variant	Exon 9 of 11		NP_001273620.1
LOC124902129	XR_007061433.1	n.3784+2670C>T		intron_variant	Intron 2 of 2
LOC124902129	XR_007061434.1	n.3879+2415C>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLLT3	ENST00000380338.9	c.1496G>A	p.Cys499Tyr	missense_variant	Exon 9 of 11	1	NM_004529.4	ENSP00000369695.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1496G>A (p.C499Y) alteration is located in exon 9 (coding exon 9) of the MLLT3 gene. This alteration results from a G to A substitution at nucleotide position 1496, causing the cysteine (C) at amino acid position 499 to be replaced by a tyrosine (Y). 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	0.18
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;T;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.47	N;.;.;N
REVEL	Uncertain	0.45
Sift	Benign	0.85	T;.;.;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.38	B;.;.;.
Vest4		0.77
MutPred		0.42		Gain of phosphorylation at C499 (P = 0.0318);.;.;.;
MVP		0.43
MPC		3.2
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.25
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-20354813;