rs28921114

Positions:

• chr17-12141985-T-TG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_003010.4(MAP2K4):​c.*728dup variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 233,360 control chromosomes in the GnomAD database, including 59 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (36 hom., cov: 32)
  • Exomes 𝑓: 0.021 (23 hom.)
• Consequence: MAP2K4 NM_003010.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K4	NM_003010.4	c.*728dup		3_prime_UTR_variant	11/11	ENST00000353533.10
MAP2K4	NM_001281435.2	c.*728dup		3_prime_UTR_variant	12/12
MAP2K4	XM_005256753.4	c.*728dup		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K4	ENST00000353533.10	c.*728dup		3_prime_UTR_variant	11/11	1	NM_003010.4	P2
MAP2K4	ENST00000415385.7	c.*728dup		3_prime_UTR_variant	12/12	2		A2
MAP2K4	ENST00000536413.2	n.2110dup		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3125 AN: 152162 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0595

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0212 AC: 1716 AN: 81080 Hom.: 23 Cov.: 0 AF XY: 0.0202 AC XY: 754 AN XY: 37314

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.00785

Gnomad4 EAS exome AF: 0.0617

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.0216

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0206 AC: 3132 AN: 152280 Hom.: 36 Cov.: 32 AF XY: 0.0209 AC XY: 1556 AN XY: 74468

Gnomad4 AFR AF: 0.0272

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.0596

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.0253

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0153 Hom.: 4

Bravo AF: 0.0219

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs28921114; hg19: chr17-12045302;