chr1-233328752-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032435.3(MAP3K21):​c.724G>C​(p.Val242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 1,372,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MAP3K21 NM_032435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3449118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K21	NM_032435.3	c.724G>C	p.Val242Leu	missense_variant	Exon 1 of 10	ENST00000366624.8	NP_115811.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K21	ENST00000366624.8	c.724G>C	p.Val242Leu	missense_variant	Exon 1 of 10	1	NM_032435.3	ENSP00000355583.3
MAP3K21	ENST00000366623.7	c.724G>C	p.Val242Leu	missense_variant	Exon 1 of 6	1		ENSP00000355582.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000722 AC: 1 AN: 138526 Hom.: 0 AF XY: 0.0000129 AC XY: 1 AN XY: 77276

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 SAS exome AF: 0.0000450

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1372066 Hom.: 0 Cov.: 31 AF XY: 0.00000589 AC XY: 4 AN XY: 679240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000514

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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	0.90	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.39	T
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.31	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0040	B;B
Vest4		0.40
MutPred		0.62		Loss of MoRF binding (P = 0.1056);Loss of MoRF binding (P = 0.1056);
MVP		0.46
MPC		2.0
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.42
gMVP		0.72

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: rs778992107; hg19: chr1-233464498;