Variant 14-50443986-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006575.6(MAP4K5):c.1390G>A(p.Ala464Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 6.9e-7 ( 0 hom. )

Consequence

MAP4K5
NM_006575.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.14

Variant links:

Genes affected

MAP4K5 (HGNC:6867): (mitogen-activated protein kinase kinase kinase kinase 5) This gene encodes a member of the serine/threonine protein kinase family, that is highly similar to yeast SPS1/STE20 kinase. Yeast SPS1/STE20 functions near the beginning of the MAP kinase signal cascades that is essential for yeast pheromone response. This kinase was shown to activate Jun kinase in mammalian cells, which suggested a role in stress response. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

MAP4K5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08331162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K5	NM_006575.6 linkuse as main transcript	c.1390G>A	p.Ala464Thr	missense_variant	19/33	ENST00000682126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MAP4K5	ENST00000682126.1 linkuse as main transcript	c.1390G>A	p.Ala464Thr	missense_variant	19/33		NM_006575.6	P1
MAP4K5	ENST00000013125.9 linkuse as main transcript	c.1390G>A	p.Ala464Thr	missense_variant	19/33	1		P1
MAP4K5	ENST00000554990.6 linkuse as main transcript	n.2143G>A		non_coding_transcript_exon_variant	5/19	2
MAP4K5	ENST00000557390.6 linkuse as main transcript	c.1390G>A	p.Ala464Thr	missense_variant, NMD_transcript_variant	19/33	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000831

AC:

AN:

240756

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

130076

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 SAS exome

AF:

0.0000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456346

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723794

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:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

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

May 18, 2023

The c.1390G>A (p.A464T) alteration is located in exon 19 (coding exon 18) of the MAP4K5 gene. This alteration results from a G to A substitution at nucleotide position 1390, causing the alanine (A) at amino acid position 464 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

0.061

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.062

Eigen

Benign

-0.18

Eigen_PC

Benign

0.059

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

M_CAP

Benign

0.011

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.79

PrimateAI

Benign

0.46

PROVEAN

Benign

0.060

REVEL

Benign

0.096

Sift

Benign

0.64

Sift4G

Benign

0.59

Polyphen

0.039

Vest4

0.057

MutPred

0.23

Gain of glycosylation at A464 (P = 0.0038);

MVP

0.47

MPC

0.25

ClinPred

0.19

GERP RS

5.4

Varity_R

0.086

gMVP

0.12

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

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