2-101766631-A-T

Variant names:

• chr2-101766631-A-T
• rs13003883
• NM_001395002.1:c.124-24089A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001395002.1(MAP4K4):​c.124-24089A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 150,606 control chromosomes in the GnomAD database, including 23,646 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 0.53 (23646 hom., cov: 29)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.69 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.124-24089A>T		intron	N/A	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.124-24089A>T		intron	N/A	NP_001371426.1
	MAP4K4	NM_001384492.1		c.124-24089A>T		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.124-24089A>T		intron	N/A	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.124-24089A>T		intron	N/A	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.124-24089A>T		intron	N/A	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80058 AN: 150506 Hom.: 23644 Cov.: 29

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.532 AC: 80060 AN: 150606 Hom.: 23646 Cov.: 29 AF XY: 0.540 AC XY: 39731 AN XY: 73602

African (AFR) AF: 0.244 AC: 9882 AN: 40492

American (AMR) AF: 0.573 AC: 8713 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2217 AN: 3472

East Asian (EAS) AF: 0.709 AC: 3658 AN: 5156

South Asian (SAS) AF: 0.650 AC: 3109 AN: 4782

European-Finnish (FIN) AF: 0.717 AC: 7428 AN: 10354

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.637 AC: 43221 AN: 67862

Other (OTH) AF: 0.553 AC: 1153 AN: 2084

Alfa AF: 0.574 Hom.: 3246

Bravo AF: 0.504

Asia WGS AF: 0.678 AC: 2352 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.7
DANN	Benign	0.67
PhyloP100		-0.20
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: rs13003883; hg19: chr2-102383093;