NM_032435.3:c.673G>C

Variant names:

• chr1-233328701-G-C
• rs1357192577
• NM_032435.3:c.673G>C

Variant summary

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

The NM_032435.3(MAP3K21):​c.673G>C​(p.Gly225Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000099 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP3K21 NM_032435.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.591
• 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=0.27391937).

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.673G>C	p.Gly225Arg	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.673G>C	p.Gly225Arg	missense	Exon 1 of 10	ENSP00000355583.3	Q5TCX8-1
	MAP3K21	ENST00000366623.7	TSL:1	c.673G>C	p.Gly225Arg	missense	Exon 1 of 6	ENSP00000355582.3	Q5TCX8-2
	MAP3K21	ENST00000915953.1		c.673G>C	p.Gly225Arg	missense	Exon 1 of 10	ENSP00000586012.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000995 AC: 12 AN: 1206234 Hom.: 0 Cov.: 31 AF XY: 0.00000507 AC XY: 3 AN XY: 591486

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000421 AC: 1 AN: 23754

American (AMR) AF: 0.0000611 AC: 1 AN: 16358

Ashkenazi Jewish (ASJ) AF: 0.0000540 AC: 1 AN: 18518

East Asian (EAS) AF: 0.0000796 AC: 2 AN: 25126

South Asian (SAS) AF: 0.00 AC: 0 AN: 51090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39948

Middle Eastern (MID) AF: 0.000285 AC: 1 AN: 3506

European-Non Finnish (NFE) AF: 0.00000510 AC: 5 AN: 980200

Other (OTH) AF: 0.0000209 AC: 1 AN: 47734

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

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	0.28
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.24	T
PhyloP100		0.59
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.13	T
Polyphen		0.79	P
Vest4		0.22
MutPred		0.48		Gain of MoRF binding (P = 0.0471)
MVP		0.67
MPC		2.9
ClinPred		0.63	D
GERP RS		0.51
Varity_R		0.14
gMVP		0.44
Mutation Taster		=90/10	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: rs1357192577; hg19: chr1-233464447;