rs4550690

Variant names:

• chr2-101806532-T-C
• rs4550690
• NM_001395002.1:c.180+15756T>C

Variant summary

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

The NM_001395002.1(MAP4K4):​c.180+15756T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,048 control chromosomes in the GnomAD database, including 5,754 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 0.16 (5754 hom., cov: 31)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.999
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP4K4	NM_001395002.1	c.180+15756T>C		intron_variant	Intron 3 of 32	ENST00000324219.9	NP_001381931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP4K4	ENST00000324219.9	c.180+15756T>C		intron_variant	Intron 3 of 32	5	NM_001395002.1	ENSP00000313644.6

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23871 AN: 151932 Hom.: 5723 Cov.: 31

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.158 AC: 23948 AN: 152048 Hom.: 5754 Cov.: 31 AF XY: 0.152 AC XY: 11299 AN XY: 74366

African (AFR) AF: 0.520 AC: 21514 AN: 41384

American (AMR) AF: 0.0869 AC: 1329 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4818

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 771 AN: 68004

Other (OTH) AF: 0.116 AC: 245 AN: 2112

Alfa AF: 0.109 Hom.: 519

Bravo AF: 0.182

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.63
DANN	Benign	0.24
PhyloP100		-1.0
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: rs4550690; hg19: chr2-102422994;