rs1567385

chr2-101698595-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001395002.1(MAP4K4):c.123+57A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,519,914 control chromosomes in the GnomAD database, including 64,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5491 hom., cov: 31)
  • Exomes 𝑓: 0.29 (59443 hom.)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.528

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-101698595-A-G is Benign according to our data. Variant chr2-101698595-A-G is described in ClinVar as [Benign]. Clinvar id is 1243012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K4	NM_001395002.1	c.123+57A>G		intron_variant		ENST00000324219.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP4K4	ENST00000324219.9	c.123+57A>G		intron_variant		5	NM_001395002.1	P3

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37393 AN: 151470 Hom.: 5490 Cov.: 31

Gnomad AFR AF: 0.0971

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.288 AC: 394055 AN: 1368326 Hom.: 59443 AF XY: 0.285 AC XY: 195308 AN XY: 685896

Gnomad4 AFR exome AF: 0.0887

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.247 AC: 37405 AN: 151588 Hom.: 5491 Cov.: 31 AF XY: 0.252 AC XY: 18615 AN XY: 74016

Gnomad4 AFR AF: 0.0970

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.247

Alfa AF: 0.278 Hom.: 6766

Bravo AF: 0.232

Asia WGS AF: 0.180 AC: 630 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 12, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	13
Dann	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs1567385; hg19: chr2-102315057; COSMIC: COSV56327797;