rs1139583

chr2-101855997-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001395002.1(MAP4K4):c.1254A>G(p.Glu418=) 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, single submitter B:1
• Conservation: PhyloP100: 0.807

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-101855997-A-G is Benign according to our data. Variant chr2-101855997-A-G is described in ClinVar as [Benign]. Clinvar id is 1183614.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
MAP4K4	NM_001395002.1	c.1254A>G	p.Glu418=	synonymous_variant	13/33	ENST00000324219.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP4K4	ENST00000324219.9	c.1254A>G	p.Glu418=	synonymous_variant	13/33	5	NM_001395002.1	P3

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

GnomAD3 exomes AF: 0.150 AC: 22990 AN: 153544 Hom.: 1888 AF XY: 0.157 AC XY: 12747 AN XY: 81408

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 SAS exome AF: 0.199

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

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0908

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.167

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.0814

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.144

Alfa AF: 0.163 Hom.: 5418

Bravo AF: 0.139

Asia WGS AF: 0.189 AC: 654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	10
Dann	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs1139583; hg19: chr2-102472459; COSMIC: COSV56341211;