Genetic Variant MAP4K4:c.123+933A>T (chr2-101699471-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001395002.1(MAP4K4):c.123+933A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 152,086 control chromosomes in the GnomAD database, including 21,853 homozygotes. 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 0.51 ( 21853 hom., cov: 32)

Consequence

MAP4K4
NM_001395002.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.144

Publications

3 publications found

Variant links:

Genes affected

MAP4K4 (HGNC:6866): (mitogen-activated protein kinase kinase kinase kinase 4) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MAP4K4 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

MAP4K4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395002.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP4K4	NM_001395002.1	MANE Select	c.123+933A>T	intron	N/A	NP_001381931.1	G5E948
MAP4K4	NM_001384497.1		c.123+933A>T	intron	N/A	NP_001371426.1
MAP4K4	NM_001384492.1		c.123+933A>T	intron	N/A	NP_001371421.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.123+933A>T	intron	N/A	ENSP00000313644.6	G5E948
MAP4K4	ENST00000350878.9	TSL:1	c.123+933A>T	intron	N/A	ENSP00000343658.5	O95819-6
MAP4K4	ENST00000347699.8	TSL:1	c.123+933A>T	intron	N/A	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes

AF:

0.505

AC:

76725

AN:

151968

Hom.:

21800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.782

Gnomad AMI

AF:

0.492

Gnomad AMR

AF:

0.430

Gnomad ASJ

AF:

0.421

Gnomad EAS

AF:

0.503

Gnomad SAS

AF:

0.543

Gnomad FIN

AF:

0.314

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.473

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.505

AC:

76825

AN:

152086

Hom.:

21853

Cov.:

AF XY:

0.502

AC XY:

37338

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.782

AC:

32460

AN:

41488

American (AMR)

AF:

0.430

AC:

6575

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

1463

AN:

3472

East Asian (EAS)

AF:

0.502

AC:

2596

AN:

5168

South Asian (SAS)

AF:

0.542

AC:

2613

AN:

4820

European-Finnish (FIN)

AF:

0.314

AC:

3316

AN:

10564

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.386

AC:

26230

AN:

67974

Other (OTH)

AF:

0.480

AC:

1010

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1732

3464

5196

6928

8660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

664

1328

1992

2656

3320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.233

Hom.:

442

Bravo

AF:

0.523

Asia WGS

AF:

0.587

AC:

2038

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

3.2

(source)

DANN

Benign

0.50

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over