17-12020945-C-T

Variant names:

• chr17-12020945-C-T
• rs978668162
• NM_003010.4:c.59C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003010.4(MAP2K4):​c.59C>T​(p.Thr20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000822 in 1,217,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: MAP2K4 NM_003010.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.867
• 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]

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]

ENSG00000293152 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09020591).
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003010.4. 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
	MAP2K4	NM_003010.4	MANE Select	c.59C>T	p.Thr20Ile	missense	Exon 1 of 11	NP_003001.1	P45985-1
	MAP2K4	NM_001281435.2		c.59C>T	p.Thr20Ile	missense	Exon 1 of 12	NP_001268364.1	P45985-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K4	ENST00000353533.10	TSL:1 MANE Select	c.59C>T	p.Thr20Ile	missense	Exon 1 of 11	ENSP00000262445.5	P45985-1
	MAP2K4	ENST00000415385.7	TSL:2	c.59C>T	p.Thr20Ile	missense	Exon 1 of 12	ENSP00000410402.3	P45985-2
	MAP2K4	ENST00000905332.1		c.59C>T	p.Thr20Ile	missense	Exon 1 of 11	ENSP00000575391.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151832 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000864 AC: 92 AN: 1065246 Hom.: 0 Cov.: 32 AF XY: 0.0000755 AC XY: 38 AN XY: 503284

African (AFR) AF: 0.0000449 AC: 1 AN: 22256

American (AMR) AF: 0.000128 AC: 1 AN: 7828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13546

East Asian (EAS) AF: 0.00 AC: 0 AN: 25240

South Asian (SAS) AF: 0.00 AC: 0 AN: 19400

European-Finnish (FIN) AF: 0.0000480 AC: 1 AN: 20852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2822

European-Non Finnish (NFE) AF: 0.0000977 AC: 89 AN: 910858

Other (OTH) AF: 0.00 AC: 0 AN: 42444

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151832 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74156

African (AFR) AF: 0.0000241 AC: 1 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.87
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.088
Sift	Uncertain	0.020	D
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.18		Loss of phosphorylation at T20 (P = 0.0011)
MVP		0.49
MPC		1.3
ClinPred		0.29	T
GERP RS		0.80
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.083
gMVP		0.23
Mutation Taster		=92/8	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: rs978668162; hg19: chr17-11924262;