Variant 19-38593286-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001042600.3(MAP4K1):c.2392C>G(p.Pro798Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,611,888 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 (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MAP4K1
NM_001042600.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

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:

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 links:

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ACMG classification

Classification made for transcript

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=0.39923143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAP4K1	NM_001042600.3 linkuse as main transcript	c.2392C>G	p.Pro798Ala	missense_variant	30/31	ENST00000396857.7	NP_001036065.1
MAP4K1	NM_007181.6 linkuse as main transcript	c.2392C>G	p.Pro798Ala	missense_variant	30/32		NP_009112.1
MAP4K1	XM_011526404.2 linkuse as main transcript	c.2512C>G	p.Pro838Ala	missense_variant	31/32		XP_011524706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K1	ENST00000396857.7 linkuse as main transcript	c.2392C>G	p.Pro798Ala	missense_variant	30/31	5	NM_001042600.3	ENSP00000380066	P1	Q92918-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459764

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000300

Hom.:

Bravo

AF:

0.0000793

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

Dec 13, 2023

The c.2392C>G (p.P798A) alteration is located in exon 30 (coding exon 30) of the MAP4K1 gene. This alteration results from a C to G substitution at nucleotide position 2392, causing the proline (P) at amino acid position 798 to be replaced by an alanine (A). 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

0.084

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.77

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.6

L;.;.;L

MutationTaster

Benign

0.65

N;N;N;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.2

.;.;.;N

REVEL

Benign

0.26

Sift

Uncertain

0.0090

.;.;.;D

Sift4G

Uncertain

0.014

D;T;D;D

Polyphen

0.87

P;.;.;D

Vest4

0.39

MutPred

0.51

Loss of sheet (P = 0.0357);.;.;Loss of sheet (P = 0.0357);

MVP

0.79

MPC

2.3

ClinPred

0.77

GERP RS

5.2

Varity_R

0.051

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

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