rs1567385

Variant names:

• chr2-101698595-A-G
• rs1567385
• NM_001395002.1:c.123+57A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.528
• Publications: 16 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 -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MAP4K4	NM_001395002.1	c.123+57A>G		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.123+57A>G		intron_variant	Intron 2 of 32	5	NM_001395002.1	ENSP00000313644.6

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

African (AFR) AF: 0.0887 AC: 2799 AN: 31546

American (AMR) AF: 0.335 AC: 14735 AN: 43938

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6377 AN: 25456

East Asian (EAS) AF: 0.249 AC: 9713 AN: 39086

South Asian (SAS) AF: 0.165 AC: 13896 AN: 84004

European-Finnish (FIN) AF: 0.421 AC: 22377 AN: 53168

Middle Eastern (MID) AF: 0.226 AC: 1253 AN: 5552

European-Non Finnish (NFE) AF: 0.299 AC: 307893 AN: 1028424

Other (OTH) AF: 0.263 AC: 15012 AN: 57152

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

African (AFR) AF: 0.0970 AC: 4011 AN: 41342

American (AMR) AF: 0.287 AC: 4379 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3466

East Asian (EAS) AF: 0.225 AC: 1148 AN: 5106

South Asian (SAS) AF: 0.162 AC: 775 AN: 4774

European-Finnish (FIN) AF: 0.433 AC: 4529 AN: 10464

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 20944 AN: 67874

Other (OTH) AF: 0.247 AC: 519 AN: 2100

Alfa AF: 0.274 Hom.: 8361

Bravo AF: 0.232

Asia WGS AF: 0.180 AC: 630 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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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
PhyloP100		0.53
PromoterAI		0.00060	Neutral
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: rs1567385; hg19: chr2-102315057; COSMIC: COSV56327797;