Variant chr19-38596432-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001042600.3(MAP4K1):c.1996C>A(p.Pro666Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000487 in 1,438,488 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

MAP4K1
NM_001042600.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.65

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:

MAP4K1 (HGNC:):

MAP4K1 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
MAP4K1	NM_001042600.3 linkuse as main transcript	c.1996C>A	p.Pro666Thr	missense_variant	26/31	ENST00000396857.7	NP_001036065.1	Q92918-2
MAP4K1	NM_007181.6 linkuse as main transcript	c.1996C>A	p.Pro666Thr	missense_variant	26/32		NP_009112.1	Q92918-1
MAP4K1	XM_011526404.2 linkuse as main transcript	c.2116C>A	p.Pro706Thr	missense_variant	27/32		XP_011524706.1
MAP4K1-AS1	NR_134907.1 linkuse as main transcript	n.86G>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K1	ENST00000396857.7 linkuse as main transcript	c.1996C>A	p.Pro666Thr	missense_variant	26/31	5	NM_001042600.3	ENSP00000380066.1		Q92918-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000487

AC:

AN:

1438488

Hom.:

Cov.:

AF XY:

0.00000420

AC XY:

AN XY:

714406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2024

The c.1996C>A (p.P666T) alteration is located in exon 26 (coding exon 26) of the MAP4K1 gene. This alteration results from a C to A substitution at nucleotide position 1996, causing the proline (P) at amino acid position 666 to be replaced by a threonine (T). 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

0.079

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.89

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Uncertain

-0.0016

MutationAssessor

Uncertain

2.0

M;.;M

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.7

.;.;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.028

.;.;D

Sift4G

Benign

0.20

T;T;T

Polyphen

0.99

D;.;D

Vest4

0.47

MutPred

0.47

Gain of catalytic residue at P666 (P = 0.0048);.;Gain of catalytic residue at P666 (P = 0.0048);

MVP

0.72

MPC

2.5

ClinPred

0.80

GERP RS

5.2

Varity_R

0.38

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -4

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over