Variant 14-50428676-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.2312G>A(p.Arg771His) variant causes a missense change. The variant allele was found at a frequency of 0.000051 in 1,510,926 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

MAP4K5
NM_006575.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.12

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=0.12187192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K5	NM_006575.6 linkuse as main transcript	c.2312G>A	p.Arg771His	missense_variant	30/33	ENST00000682126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MAP4K5	ENST00000682126.1 linkuse as main transcript	c.2312G>A	p.Arg771His	missense_variant	30/33		NM_006575.6	P1
MAP4K5	ENST00000013125.9 linkuse as main transcript	c.2312G>A	p.Arg771His	missense_variant	30/33	1		P1
MAP4K5	ENST00000554990.6 linkuse as main transcript	n.3065G>A		non_coding_transcript_exon_variant	16/19	2
MAP4K5	ENST00000557390.6 linkuse as main transcript	c.*133G>A		3_prime_UTR_variant, NMD_transcript_variant	30/33	3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000955

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

141320

Hom.:

AF XY:

0.0000661

AC XY:

AN XY:

75644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000485

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000178

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000279

GnomAD4 exome

AF:

0.0000441

AC:

AN:

1359050

Hom.:

Cov.:

AF XY:

0.0000461

AC XY:

AN XY:

672088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000344

Gnomad4 AMR exome

AF:

0.000165

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000279

Gnomad4 FIN exome

AF:

0.000121

Gnomad4 NFE exome

AF:

0.0000282

Gnomad4 OTH exome

AF:

0.000107

GnomAD4 genome

AF:

0.000112

AC:

AN:

151876

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74188

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000955

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000815

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000257

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3476

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

Aug 16, 2021

The c.2312G>A (p.R771H) alteration is located in exon 30 (coding exon 29) of the MAP4K5 gene. This alteration results from a G to A substitution at nucleotide position 2312, causing the arginine (R) at amino acid position 771 to be replaced by a histidine (H). 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

0.066

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.051

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0071

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.81

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.78

REVEL

Benign

0.13

Sift

Benign

0.18

Sift4G

Benign

0.16

Polyphen

0.96

Vest4

0.20

MVP

0.39

MPC

0.43

ClinPred

0.090

GERP RS

5.9

Varity_R

0.072

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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