NM_001395002.1:c.57+38delA

Variant names:

• chr2-101698174-CA-C
• rs375488010
• NM_001395002.1:c.57+38delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001395002.1(MAP4K4):​c.57+38delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 920,490 control chromosomes in the GnomAD database, including 1,195 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.065 (808 hom., cov: 31)
  • Exomes 𝑓: 0.015 (387 hom.)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.220
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-101698174-CA-C is Benign according to our data. Variant chr2-101698174-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1221787.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	NM_001395002.1	MANE Select	c.57+38delA		intron	N/A	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.57+38delA		intron	N/A	NP_001371426.1
	MAP4K4	NM_001384492.1		c.57+38delA		intron	N/A	NP_001371421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.57+38delA		intron	N/A	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.57+38delA		intron	N/A	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.57+38delA		intron	N/A	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9465 AN: 146412 Hom.: 809 Cov.: 31

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0199

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.00442

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000238

Gnomad MID AF: 0.0226

Gnomad NFE AF: 0.00925

Gnomad OTH AF: 0.0519

GnomAD2 exomes AF: 0.0402 AC: 1561 AN: 38874 AF XY: 0.0339

Gnomad AFR exome AF: 0.430

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000497

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0539

GnomAD4 exome AF: 0.0150 AC: 11639 AN: 773972 Hom.: 387 Cov.: 12 AF XY: 0.0149 AC XY: 5480 AN XY: 368882

African (AFR) AF: 0.222 AC: 3449 AN: 15526

American (AMR) AF: 0.0801 AC: 189 AN: 2360

Ashkenazi Jewish (ASJ) AF: 0.00928 AC: 56 AN: 6032

East Asian (EAS) AF: 0.00 AC: 0 AN: 4212

South Asian (SAS) AF: 0.00440 AC: 98 AN: 22248

European-Finnish (FIN) AF: 0.000456 AC: 7 AN: 15348

Middle Eastern (MID) AF: 0.0208 AC: 53 AN: 2548

European-Non Finnish (NFE) AF: 0.0107 AC: 7273 AN: 680294

Other (OTH) AF: 0.0202 AC: 514 AN: 25404

GnomAD4 genome AF: 0.0647 AC: 9481 AN: 146518 Hom.: 808 Cov.: 31 AF XY: 0.0625 AC XY: 4461 AN XY: 71328

African (AFR) AF: 0.194 AC: 7957 AN: 40958

American (AMR) AF: 0.0511 AC: 757 AN: 14800

Ashkenazi Jewish (ASJ) AF: 0.00442 AC: 15 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4810

European-Finnish (FIN) AF: 0.000238 AC: 2 AN: 8416

Middle Eastern (MID) AF: 0.0208 AC: 6 AN: 288

European-Non Finnish (NFE) AF: 0.00927 AC: 610 AN: 65838

Other (OTH) AF: 0.0514 AC: 105 AN: 2044

Alfa AF: 0.00312 Hom.: 5

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs375488010; hg19: chr2-102314636;