rs17205284

Variant names:

• chr2-101786476-C-T
• rs17205284
• NM_001395002.1:c.124-4244C>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.124-4244C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0672 in 152,010 control chromosomes in the GnomAD database, including 473 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 0.067 (473 hom., cov: 31)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 4 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 (NFE) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP4K4	NM_001395002.1	c.124-4244C>T		intron_variant	Intron 2 of 32	ENST00000324219.9	NP_001381931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP4K4	ENST00000324219.9	c.124-4244C>T		intron_variant	Intron 2 of 32	5	NM_001395002.1	ENSP00000313644.6

Frequencies

GnomAD3 genomes AF: 0.0673 AC: 10216 AN: 151904 Hom.: 472 Cov.: 31

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0634

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0758

Gnomad FIN AF: 0.0977

Gnomad MID AF: 0.0577

Gnomad NFE AF: 0.0988

Gnomad OTH AF: 0.0593

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

GnomAD4 genome AF: 0.0672 AC: 10220 AN: 152010 Hom.: 473 Cov.: 31 AF XY: 0.0658 AC XY: 4885 AN XY: 74288

African (AFR) AF: 0.0184 AC: 764 AN: 41466

American (AMR) AF: 0.0636 AC: 971 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5164

South Asian (SAS) AF: 0.0765 AC: 368 AN: 4808

European-Finnish (FIN) AF: 0.0977 AC: 1030 AN: 10538

Middle Eastern (MID) AF: 0.0586 AC: 17 AN: 290

European-Non Finnish (NFE) AF: 0.0988 AC: 6716 AN: 67974

Other (OTH) AF: 0.0588 AC: 124 AN: 2110

Alfa AF: 0.0565 Hom.: 95

Bravo AF: 0.0614

Asia WGS AF: 0.0340 AC: 120 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	0.33
DANN	Benign	0.74
PhyloP100		-1.3
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: rs17205284; hg19: chr2-102402938;