chr17-12020956-G-A

Variant names:

• chr17-12020956-G-A
• NM_003010.4:c.70G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003010.4(MAP2K4):​c.70G>A​(p.Val24Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000981 in 1,019,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V24A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: MAP2K4 NM_003010.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.612
• Publications: 0 publications found

Genes affected

MAP2K4 (HGNC:6844): (mitogen-activated protein kinase kinase 4) This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ENSG00000293152 (HGNC:):

ZNF18 (HGNC:12969): (zinc finger protein 18) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054358184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K4	NM_003010.4	c.70G>A	p.Val24Ile	missense_variant	Exon 1 of 11	ENST00000353533.10	NP_003001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K4	ENST00000353533.10	c.70G>A	p.Val24Ile	missense_variant	Exon 1 of 11	1	NM_003010.4	ENSP00000262445.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.81e-7 AC: 1 AN: 1019682 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 480882

African (AFR) AF: 0.00 AC: 0 AN: 20738

American (AMR) AF: 0.00 AC: 0 AN: 6376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11546

East Asian (EAS) AF: 0.00 AC: 0 AN: 21742

South Asian (SAS) AF: 0.00 AC: 0 AN: 18974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2546

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 882860

Other (OTH) AF: 0.00 AC: 0 AN: 39118

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70G>A (p.V24I) alteration is located in exon 1 (coding exon 1) of the MAP2K4 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the valine (V) at amino acid position 24 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.58	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		0.61
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.13
Sift	Benign	0.44	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;B
Vest4		0.10
MutPred		0.16		Gain of stability (P = 0.2053);Gain of stability (P = 0.2053);
MVP		0.35
MPC		0.98
ClinPred		0.077	T
GERP RS		1.3
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.027
gMVP		0.13
Mutation Taster		=91/9	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

hg19: chr17-11924273;