Genetic Variant MAP4K1:p.Ala452Thr (chr19-38605577-C-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_001042600.3(MAP4K1):c.1354G>A(p.Ala452Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000782 in 1,534,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A452S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

MAP4K1
NM_001042600.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.56

Publications

2 publications found

Variant links:

Genes affected

MAP4K1 (HGNC:6863): (mitogen-activated protein kinase kinase kinase kinase 1) Enables ATP binding activity and MAP kinase kinase kinase kinase activity. Involved in several processes, including JNK cascade; cellular response to phorbol 13-acetate 12-myristate; and protein phosphorylation. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

MAP4K1 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=0.28718364).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042600.3. 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
	MAP4K1	NM_001042600.3	MANE Select	c.1354G>A	p.Ala452Thr	missense	Exon 18 of 31	NP_001036065.1	Q92918-2
	MAP4K1	NM_007181.6		c.1354G>A	p.Ala452Thr	missense	Exon 18 of 32	NP_009112.1	Q92918-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP4K1	ENST00000396857.7	TSL:5 MANE Select	c.1354G>A	p.Ala452Thr	missense	Exon 18 of 31	ENSP00000380066.1	Q92918-2
MAP4K1	ENST00000591517.5	TSL:1	c.1354G>A	p.Ala452Thr	missense	Exon 18 of 32	ENSP00000465039.1	Q92918-1
MAP4K1	ENST00000864511.1		c.1474G>A	p.Ala492Thr	missense	Exon 19 of 32	ENSP00000534570.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000707

AC:

AN:

141520

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000651

AC:

AN:

1383294

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

683444

show subpopulations

African (AFR)

AF:

0.0000653

AC:

AN:

30618

American (AMR)

AF:

0.00

AC:

AN:

29438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23818

East Asian (EAS)

AF:

0.00

AC:

AN:

36078

South Asian (SAS)

AF:

0.00

AC:

AN:

78294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5462

European-Non Finnish (NFE)

AF:

0.00000652

AC:

AN:

1074314

Other (OTH)

AF:

0.00

AC:

AN:

57166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.0000198

AC:

AN:

151460

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73934

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41174

American (AMR)

AF:

0.0000659

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.80

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.2

PhyloP100

4.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.72

REVEL

Benign

0.11

Sift

Benign

0.47

Sift4G

Benign

0.42

Polyphen

0.99

Vest4

0.36

MVP

0.85

MPC

0.62

ClinPred

0.87

GERP RS

5.2

Varity_R

0.10

gMVP

0.23

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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