rs1139583

Variant names:

• chr2-101855997-A-G
• rs1139583
• NM_001395002.1:c.1254A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001395002.1(MAP4K4):​c.1254A>G​(p.Glu418Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,549,936 control chromosomes in the GnomAD database, including 21,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1722 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19460 hom.)
• Consequence: MAP4K4 NM_001395002.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.807
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.03).
• BP6: Variant 2-101855997-A-G is Benign according to our data. Variant chr2-101855997-A-G is described in ClinVar as Benign. ClinVar VariationId is 1183614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.807 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP4K4	NM_001395002.1	c.1254A>G	p.Glu418Glu	synonymous_variant	Exon 13 of 33	ENST00000324219.9	NP_001381931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP4K4	ENST00000324219.9	c.1254A>G	p.Glu418Glu	synonymous_variant	Exon 13 of 33	5	NM_001395002.1	ENSP00000313644.6

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22146 AN: 152062 Hom.: 1721 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0820

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.150 AC: 22990 AN: 153544 AF XY: 0.157

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0859

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.0727

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.164 AC: 228656 AN: 1397756 Hom.: 19460 Cov.: 32 AF XY: 0.166 AC XY: 114205 AN XY: 689492

African (AFR) AF: 0.119 AC: 3730 AN: 31362

American (AMR) AF: 0.0908 AC: 3203 AN: 35264

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5408 AN: 25126

East Asian (EAS) AF: 0.102 AC: 3647 AN: 35864

South Asian (SAS) AF: 0.198 AC: 15685 AN: 79026

European-Finnish (FIN) AF: 0.152 AC: 7493 AN: 49248

Middle Eastern (MID) AF: 0.225 AC: 1278 AN: 5678

European-Non Finnish (NFE) AF: 0.166 AC: 178567 AN: 1078276

Other (OTH) AF: 0.167 AC: 9645 AN: 57912

GnomAD4 genome AF: 0.146 AC: 22147 AN: 152180 Hom.: 1722 Cov.: 32 AF XY: 0.146 AC XY: 10881 AN XY: 74392

African (AFR) AF: 0.119 AC: 4922 AN: 41506

American (AMR) AF: 0.121 AC: 1851 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 751 AN: 3468

East Asian (EAS) AF: 0.0814 AC: 421 AN: 5174

South Asian (SAS) AF: 0.196 AC: 944 AN: 4824

European-Finnish (FIN) AF: 0.147 AC: 1559 AN: 10592

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11159 AN: 68000

Other (OTH) AF: 0.144 AC: 304 AN: 2112

Alfa AF: 0.159 Hom.: 9938

Bravo AF: 0.139

Asia WGS AF: 0.189 AC: 654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.53
PhyloP100		0.81
PromoterAI		-0.0031	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1139583; hg19: chr2-102472459; COSMIC: COSV56341211;