rs972372

Variant names:

• chr2-101850859-T-C
• rs972372
• NM_001395002.1:c.1234-5118T>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.1234-5118T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 152,120 control chromosomes in the GnomAD database, including 35,628 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 0.67 (35628 hom., cov: 33)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.251
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.831 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.1234-5118T>C		intron	N/A	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.1234-5118T>C		intron	N/A	NP_001371426.1
	MAP4K4	NM_001384492.1		c.1234-5118T>C		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.1234-5118T>C		intron	N/A	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.1234-5118T>C		intron	N/A	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.1234-5118T>C		intron	N/A	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102522 AN: 152002 Hom.: 35570 Cov.: 33

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.648

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

GnomAD4 genome AF: 0.675 AC: 102645 AN: 152120 Hom.: 35628 Cov.: 33 AF XY: 0.676 AC XY: 50252 AN XY: 74386

African (AFR) AF: 0.838 AC: 34806 AN: 41510

American (AMR) AF: 0.654 AC: 10000 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1905 AN: 3468

East Asian (EAS) AF: 0.494 AC: 2556 AN: 5176

South Asian (SAS) AF: 0.501 AC: 2421 AN: 4830

European-Finnish (FIN) AF: 0.696 AC: 7360 AN: 10582

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41535 AN: 67952

Other (OTH) AF: 0.643 AC: 1356 AN: 2110

Alfa AF: 0.619 Hom.: 45510

Bravo AF: 0.681

Asia WGS AF: 0.550 AC: 1914 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.3
DANN	Benign	0.70
PhyloP100		0.25
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: rs972372; hg19: chr2-102467321; COSMIC: COSV56328144;