Variant 19-38597337-G-A 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.1826C>T(p.Ala609Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MAP4K1
NM_001042600.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

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-AS1 (HGNC:55302): (MAP4K1 antisense RNA 1)

MAP4K1-AS1 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=0.30480984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAP4K1	NM_001042600.3 linkuse as main transcript	c.1826C>T	p.Ala609Val	missense_variant	24/31	ENST00000396857.7	NP_001036065.1
MAP4K1-AS1	NR_134907.1 linkuse as main transcript	n.175G>A		non_coding_transcript_exon_variant	2/3
MAP4K1	NM_007181.6 linkuse as main transcript	c.1826C>T	p.Ala609Val	missense_variant	24/32		NP_009112.1
MAP4K1	XM_011526404.2 linkuse as main transcript	c.1946C>T	p.Ala649Val	missense_variant	25/32		XP_011524706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K1	ENST00000396857.7 linkuse as main transcript	c.1826C>T	p.Ala609Val	missense_variant	24/31	5	NM_001042600.3	ENSP00000380066	P1	Q92918-2
MAP4K1-AS1	ENST00000589557.1 linkuse as main transcript	n.176G>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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 07, 2021

The c.1826C>T (p.A609V) alteration is located in exon 24 (coding exon 24) of the MAP4K1 gene. This alteration results from a C to T substitution at nucleotide position 1826, causing the alanine (A) at amino acid position 609 to be replaced by a valine (V). 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

0.16

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.40

M_CAP

Benign

0.025

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;.;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.6

.;.;N

REVEL

Benign

0.086

Sift

Uncertain

0.010

.;.;D

Sift4G

Uncertain

0.019

D;D;D

Polyphen

0.32

B;.;B

Vest4

0.53

MutPred

0.58

Gain of methylation at K605 (P = 0.1506);.;Gain of methylation at K605 (P = 0.1506);

MVP

0.47

MPC

1.9

ClinPred

0.90

GERP RS

3.1

Varity_R

0.13

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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