Variant 14-50442751-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006575.6(MAP4K5):c.1545G>T(p.Trp515Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,446,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

MAP4K5
NM_006575.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.05

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K5	NM_006575.6 linkuse as main transcript	c.1545G>T	p.Trp515Cys	missense_variant	21/33	ENST00000682126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MAP4K5	ENST00000682126.1 linkuse as main transcript	c.1545G>T	p.Trp515Cys	missense_variant	21/33		NM_006575.6	P1
MAP4K5	ENST00000013125.9 linkuse as main transcript	c.1545G>T	p.Trp515Cys	missense_variant	21/33	1		P1
MAP4K5	ENST00000554990.6 linkuse as main transcript	n.2298G>T		non_coding_transcript_exon_variant	7/19	2
MAP4K5	ENST00000557390.6 linkuse as main transcript	c.1545G>T	p.Trp515Cys	missense_variant, NMD_transcript_variant	21/33	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1446156

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719112

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:

9.05e-7

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

May 04, 2022

The c.1545G>T (p.W515C) alteration is located in exon 21 (coding exon 20) of the MAP4K5 gene. This alteration results from a G to T substitution at nucleotide position 1545, causing the tryptophan (W) at amino acid position 515 to be replaced by a cysteine (C). 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-12

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.87

MutPred

0.63

Gain of catalytic residue at D519 (P = 0.0011);

MVP

0.96

MPC

1.2

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over