NM_001395002.1:c.57+163C>T

Variant names:

• chr2-101698300-C-T
• rs560675155
• NM_001395002.1:c.57+163C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001395002.1(MAP4K4):​c.57+163C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 150,728 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.012 (45 hom., cov: 31)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.79
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-101698300-C-T is Benign according to our data. Variant chr2-101698300-C-T is described in ClinVar as Benign. ClinVar VariationId is 1283903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1880 AD gene.

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.57+163C>T		intron	N/A	NP_001381931.1	G5E948
	MAP4K4	NM_001384564.1		c.-143C>T		5_prime_UTR	Exon 1 of 31	NP_001371493.1
	MAP4K4	NM_001384555.1		c.-143C>T		5_prime_UTR	Exon 1 of 31	NP_001371484.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.57+163C>T		intron	N/A	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.57+163C>T		intron	N/A	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.57+163C>T		intron	N/A	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1880 AN: 150620 Hom.: 45 Cov.: 31

Gnomad AFR AF: 0.00216

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00721

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0125 AC: 1880 AN: 150728 Hom.: 45 Cov.: 31 AF XY: 0.0146 AC XY: 1077 AN XY: 73632

African (AFR) AF: 0.00215 AC: 89 AN: 41404

American (AMR) AF: 0.00217 AC: 33 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0734 AC: 733 AN: 9980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0148 AC: 1001 AN: 67502

Other (OTH) AF: 0.00714 AC: 15 AN: 2102

Alfa AF: 0.0140 Hom.: 5

Bravo AF: 0.00679

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	-0.75
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		1.8
PromoterAI		-0.0056	Neutral
Mutation Taster		=100/0	polymorphism

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: rs560675155; hg19: chr2-102314762;