12-111870307-A-C

Variant names:

• chr12-111870307-A-C
• rs199721843
• NM_003668.4:c.430A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003668.4(MAPKAPK5):​c.430A>C​(p.Ile144Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000975 in 1,611,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (0 hom.)
• Consequence: MAPKAPK5 NM_003668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02
• Publications: 5 publications found

Genes affected

MAPKAPK5 (HGNC:6889): (MAPK activated protein kinase 5) The protein encoded by this gene is a tumor suppressor and member of the serine/threonine kinase family. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. The encoded protein is found in the nucleus but translocates to the cytoplasm upon phosphorylation and activation. This kinase phosphorylates heat shock protein HSP27 at its physiologically relevant sites. Two alternately spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2012]

MAPKAPK5 Gene-Disease associations (from GenCC):

• neurocardiofaciodigital syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021787226).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000959 (146/152278) while in subpopulation AMR AF = 0.0019 (29/15288). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003668.4. 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
	MAPKAPK5	NM_003668.4	MANE Select	c.430A>C	p.Ile144Leu	missense	Exon 6 of 14	NP_003659.2
	MAPKAPK5	NM_001371479.1		c.430A>C	p.Ile144Leu	missense	Exon 6 of 16	NP_001358408.1
	MAPKAPK5	NM_001371480.1		c.430A>C	p.Ile144Leu	missense	Exon 6 of 16	NP_001358409.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK5	ENST00000550735.7	TSL:1 MANE Select	c.430A>C	p.Ile144Leu	missense	Exon 6 of 14	ENSP00000449667.2	Q8IW41-2
	MAPKAPK5	ENST00000551404.7	TSL:5	c.430A>C	p.Ile144Leu	missense	Exon 6 of 14	ENSP00000449381.2	Q8IW41-1
	MAPKAPK5	ENST00000549875.1	TSL:5	c.37-778A>C		intron	N/A	ENSP00000473467.1	R4GN33

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 146 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.000899 AC: 224 AN: 249054 AF XY: 0.000792

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000977 AC: 1425 AN: 1458764 Hom.: 0 Cov.: 30 AF XY: 0.000994 AC XY: 721 AN XY: 725174

African (AFR) AF: 0.000239 AC: 8 AN: 33452

American (AMR) AF: 0.00188 AC: 84 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86170

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53340

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5752

European-Non Finnish (NFE) AF: 0.00112 AC: 1244 AN: 1109406

Other (OTH) AF: 0.000929 AC: 56 AN: 60262

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74462

African (AFR) AF: 0.000457 AC: 19 AN: 41552

American (AMR) AF: 0.00190 AC: 29 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68024

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.00107

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.000974 AC: 8

ExAC AF: 0.000993 AC: 120

EpiCase AF: 0.00153

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.082
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.047	D
Polyphen		0.0	B
Vest4		0.56
MVP		0.81
MPC		0.54
ClinPred		0.028	T
GERP RS		4.4
Varity_R		0.42
gMVP		0.54
Mutation Taster		=74/26	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: rs199721843; hg19: chr12-112308111;