Variant 14-50445113-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006575.6(MAP4K5):c.1267A>G(p.Ser423Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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: 0.000015 ( 0 hom. )

Consequence

MAP4K5
NM_006575.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047103018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K5	NM_006575.6 linkuse as main transcript	c.1267A>G	p.Ser423Gly	missense_variant	18/33	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.1267A>G	p.Ser423Gly	missense_variant	18/33		NM_006575.6	ENSP00000507200.1	A0A804HIS2
MAP4K5	ENST00000013125.9 linkuse as main transcript	c.1267A>G	p.Ser423Gly	missense_variant	18/33	1		ENSP00000013125.5	Q9Y4K4
MAP4K5	ENST00000554990.6 linkuse as main transcript	n.2020A>G		non_coding_transcript_exon_variant	4/19	2
MAP4K5	ENST00000557390.6 linkuse as main transcript	n.1267A>G		non_coding_transcript_exon_variant	18/33	3		ENSP00000451980.2	G3V4T8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152240

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:

0.0000161

AC:

AN:

248708

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134938

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461402

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

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

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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 15, 2024

The c.1267A>G (p.S423G) alteration is located in exon 18 (coding exon 17) of the MAP4K5 gene. This alteration results from a A to G substitution at nucleotide position 1267, causing the serine (S) at amino acid position 423 to be replaced by a glycine (G). 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

0.063

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.14

M_CAP

Benign

0.0047

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.89

REVEL

Benign

0.040

Sift

Benign

0.28

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.089

MutPred

0.24

Gain of catalytic residue at P419 (P = 0.0028);

MVP

0.25

MPC

0.23

ClinPred

0.028

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.074

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