Genetic Variant NM_001395002.1:c.-363_-362dupTC (chr2-101697716-A-ACT) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_001395002.1(MAP4K4):c.-363_-362dupTC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.75 ( 41493 hom., cov: 0)

Exomes 𝑓: 0.67 ( 197 hom. )

Consequence

MAP4K4
NM_001395002.1 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.529

Publications

0 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 -10 ACMG points.

BP6

Variant 2-101697716-A-ACT is Benign according to our data. Variant chr2-101697716-A-ACT is described in ClinVar as Benign. ClinVar VariationId is 1225314.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.872 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.-363_-362dupTC	5_prime_UTR	Exon 1 of 33	NP_001381931.1	G5E948
MAP4K4	NM_001384497.1		c.-363_-362dupTC	5_prime_UTR	Exon 1 of 32	NP_001371426.1
MAP4K4	NM_001384492.1		c.-363_-362dupTC	5_prime_UTR	Exon 1 of 33	NP_001371421.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.-363_-362dupTC	5_prime_UTR	Exon 1 of 33	ENSP00000313644.6	G5E948
MAP4K4	ENST00000902131.1		c.-363_-362dupTC	5_prime_UTR	Exon 1 of 31	ENSP00000572190.1
MAP4K4	ENST00000971084.1		c.-363_-362dupTC	5_prime_UTR	Exon 1 of 31	ENSP00000641143.1

Frequencies

GnomAD3 genomes

AF:

0.754

AC:

108914

AN:

144460

Hom.:

41446

Cov.:

show subpopulations

Gnomad AFR

AF:

0.879

Gnomad AMI

AF:

0.673

Gnomad AMR

AF:

0.718

Gnomad ASJ

AF:

0.666

Gnomad EAS

AF:

0.786

Gnomad SAS

AF:

0.710

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.672

Gnomad NFE

AF:

0.694

Gnomad OTH

AF:

0.729

GnomAD4 exome

AF:

0.667

AC:

574

AN:

860

Hom.:

197

Cov.:

AF XY:

0.650

AC XY:

277

AN XY:

426

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.668

AC:

548

AN:

820

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.607

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.754

AC:

109003

AN:

144546

Hom.:

41493

Cov.:

AF XY:

0.757

AC XY:

53204

AN XY:

70310

show subpopulations

African (AFR)

AF:

0.879

AC:

35257

AN:

40090

American (AMR)

AF:

0.717

AC:

10542

AN:

14694

Ashkenazi Jewish (ASJ)

AF:

0.666

AC:

2266

AN:

3400

East Asian (EAS)

AF:

0.785

AC:

3718

AN:

4734

South Asian (SAS)

AF:

0.710

AC:

3300

AN:

4648

European-Finnish (FIN)

AF:

0.747

AC:

6276

AN:

8398

Middle Eastern (MID)

AF:

0.678

AC:

194

AN:

286

European-Non Finnish (NFE)

AF:

0.694

AC:

45405

AN:

65432

Other (OTH)

AF:

0.732

AC:

1465

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1184

2368

3553

4737

5921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.654

Hom.:

3188

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.53

Splicing

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