Genetic Variant MLLT1:p.Ser440Arg (chr19-6214026-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005934.4(MLLT1):c.1320C>A(p.Ser440Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,294,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S440S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

MLLT1
NM_005934.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.146

Publications

0 publications found

Variant links:

Genes affected

MLLT1 (HGNC:7134): (MLLT1 super elongation complex subunit) Predicted to be involved in regulation of transcription, DNA-templated. Predicted to act upstream of or within negative regulation of protein kinase activity. Located in cytosol; fibrillar center; and nucleoplasm. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

MLLT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4072257).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005934.4. 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
	MLLT1	NM_005934.4	MANE Select	c.1320C>A	p.Ser440Arg	missense	Exon 9 of 12	NP_005925.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLLT1	ENST00000252674.9	TSL:1 MANE Select	c.1320C>A	p.Ser440Arg	missense	Exon 9 of 12	ENSP00000252674.6	Q03111
MLLT1	ENST00000867663.1		c.1194C>A	p.Ser398Arg	missense	Exon 8 of 11	ENSP00000537722.1
MLLT1	ENST00000943587.1		c.1191C>A	p.Ser397Arg	missense	Exon 8 of 11	ENSP00000613646.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000155

AC:

AN:

1294444

Hom.:

Cov.:

AF XY:

0.00000319

AC XY:

AN XY:

627772

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28406

American (AMR)

AF:

0.00

AC:

AN:

20704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18448

East Asian (EAS)

AF:

0.0000286

AC:

AN:

34986

South Asian (SAS)

AF:

0.0000172

AC:

AN:

58184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3562

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1033634

Other (OTH)

AF:

0.00

AC:

AN:

53300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.033

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.7

PhyloP100

-0.15

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.2

REVEL

Benign

0.21

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.51

MutPred

0.33

Loss of phosphorylation at S440 (P = 0.0022)

MVP

0.48

MPC

0.39

ClinPred

0.98

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.38

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over