rs17801985

Variant names:

• chr2-101842806-A-G
• rs17801985
• NM_001395002.1:c.1022+125A>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.1022+125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 612,446 control chromosomes in the GnomAD database, including 14,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2967 hom., cov: 32)
  • Exomes 𝑓: 0.20 (11379 hom.)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.94
• Publications: 5 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=-0.9).
• BP6: Variant 2-101842806-A-G is Benign according to our data. Variant chr2-101842806-A-G is described in ClinVar as Benign. ClinVar VariationId is 1240478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 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.1022+125A>G		intron	N/A	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.1022+125A>G		intron	N/A	NP_001371426.1
	MAP4K4	NM_001384492.1		c.1022+125A>G		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.1022+125A>G		intron	N/A	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.1022+125A>G		intron	N/A	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.1022+125A>G		intron	N/A	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26150 AN: 152046 Hom.: 2967 Cov.: 32

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0651

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.201 AC: 92675 AN: 460282 Hom.: 11379 AF XY: 0.197 AC XY: 47495 AN XY: 240606

African (AFR) AF: 0.0635 AC: 774 AN: 12188

American (AMR) AF: 0.111 AC: 2001 AN: 18030

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 2114 AN: 12714

East Asian (EAS) AF: 0.000980 AC: 28 AN: 28564

South Asian (SAS) AF: 0.0731 AC: 2422 AN: 33126

European-Finnish (FIN) AF: 0.326 AC: 13396 AN: 41140

Middle Eastern (MID) AF: 0.127 AC: 314 AN: 2470

European-Non Finnish (NFE) AF: 0.234 AC: 67207 AN: 286834

Other (OTH) AF: 0.175 AC: 4419 AN: 25216

GnomAD4 genome AF: 0.172 AC: 26154 AN: 152164 Hom.: 2967 Cov.: 32 AF XY: 0.173 AC XY: 12879 AN XY: 74376

African (AFR) AF: 0.0671 AC: 2787 AN: 41534

American (AMR) AF: 0.129 AC: 1981 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 601 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0653 AC: 315 AN: 4822

European-Finnish (FIN) AF: 0.331 AC: 3492 AN: 10560

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16472 AN: 67978

Other (OTH) AF: 0.164 AC: 346 AN: 2108

Alfa AF: 0.226 Hom.: 1494

Bravo AF: 0.150

Asia WGS AF: 0.0420 AC: 150 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.010
DANN	Benign	0.44
PhyloP100		-1.9
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: rs17801985; hg19: chr2-102459268;