Variant 14-50434497-C-G 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.2061G>C(p.Met687Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,607,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MAP4K5
NM_006575.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.26

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:

MAP4K5 (HGNC:):

MAP4K5 links:

Genome browser will be placed here

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=0.19167629).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K5	NM_006575.6 linkuse as main transcript	c.2061G>C	p.Met687Ile	missense_variant	28/33	ENST00000682126.1	NP_006566.2	Q9Y4K4A0A804HIS2B3KWC4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MAP4K5	ENST00000682126.1 linkuse as main transcript	c.2061G>C	p.Met687Ile	missense_variant	28/33		NM_006575.6	ENSP00000507200.1	A0A804HIS2
MAP4K5	ENST00000013125.9 linkuse as main transcript	c.2061G>C	p.Met687Ile	missense_variant	28/33	1		ENSP00000013125.5	Q9Y4K4
MAP4K5	ENST00000554990.6 linkuse as main transcript	n.2814G>C		non_coding_transcript_exon_variant	14/19	2
MAP4K5	ENST00000557390.6 linkuse as main transcript	n.2061G>C		non_coding_transcript_exon_variant	28/33	3		ENSP00000451980.2	G3V4T8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000839

AC:

AN:

238512

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

128788

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1455396

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

723092

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:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

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

Nov 10, 2024

The c.2061G>C (p.M687I) alteration is located in exon 28 (coding exon 27) of the MAP4K5 gene. This alteration results from a G to C substitution at nucleotide position 2061, causing the methionine (M) at amino acid position 687 to be replaced by an isoleucine (I). 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

Uncertain

0.55

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.071

Eigen

Benign

-0.18

Eigen_PC

Benign

0.043

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.014

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.34

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.2

REVEL

Benign

0.13

Sift

Benign

0.51

Sift4G

Benign

0.60

Polyphen

0.080

Vest4

0.39

MutPred

0.47

Gain of catalytic residue at Q683 (P = 0);

MVP

0.26

MPC

0.28

ClinPred

0.37

GERP RS

5.0

Varity_R

0.23

gMVP

0.15

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