1-233328752-G-T

Variant names:

• chr1-233328752-G-T
• rs778992107
• NM_032435.3:c.724G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032435.3(MAP3K21):​c.724G>T​(p.Val242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,524,060 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: MAP3K21 NM_032435.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64
• Publications: 0 publications found

Genes affected

MAP3K21 (HGNC:29798): (mitogen-activated protein kinase kinase kinase 21) Predicted to enable protein homodimerization activity and protein kinase activity. Predicted to be involved in protein autophosphorylation and signal transduction. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31486696).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032435.3. 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
	MAP3K21	NM_032435.3	MANE Select	c.724G>T	p.Val242Leu	missense	Exon 1 of 10	NP_115811.2	Q5TCX8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K21	ENST00000366624.8	TSL:1 MANE Select	c.724G>T	p.Val242Leu	missense	Exon 1 of 10	ENSP00000355583.3	Q5TCX8-1
	MAP3K21	ENST00000366623.7	TSL:1	c.724G>T	p.Val242Leu	missense	Exon 1 of 6	ENSP00000355582.3	Q5TCX8-2
	MAP3K21	ENST00000915953.1		c.724G>T	p.Val242Leu	missense	Exon 1 of 10	ENSP00000586012.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000144 AC: 2 AN: 138526 AF XY: 0.0000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000375

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000321 AC: 44 AN: 1372066 Hom.: 0 Cov.: 31 AF XY: 0.0000353 AC XY: 24 AN XY: 679240

African (AFR) AF: 0.00 AC: 0 AN: 28666

American (AMR) AF: 0.00 AC: 0 AN: 34670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24034

East Asian (EAS) AF: 0.00 AC: 0 AN: 31130

South Asian (SAS) AF: 0.00 AC: 0 AN: 77760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.0000403 AC: 43 AN: 1066422

Other (OTH) AF: 0.0000178 AC: 1 AN: 56186

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74254

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.000131 AC: 2 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67966

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000173 AC: 2

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	0.31
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.39	T
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.54
Sift	Benign	0.31	T
Sift4G	Benign	0.56	T
Polyphen		0.0040	B
Vest4		0.40
MutPred		0.62		Loss of MoRF binding (P = 0.1056)
MVP		0.46
MPC		2.0
ClinPred		0.54	D
GERP RS		4.0
Varity_R		0.42
gMVP		0.72
Mutation Taster		=35/65	disease causing

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: rs778992107; hg19: chr1-233464498;