1-233328701-G-T

Variant names:

• chr1-233328701-G-T
• rs1357192577
• NM_032435.3:c.673G>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.673G>T​(p.Gly225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,206,266 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G225R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: MAP3K21 NM_032435.3 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.35364333).

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>T	p.Gly225Cys	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>T	p.Gly225Cys	missense	Exon 1 of 10	ENSP00000355583.3	Q5TCX8-1
	MAP3K21	ENST00000366623.7	TSL:1	c.673G>T	p.Gly225Cys	missense	Exon 1 of 6	ENSP00000355582.3	Q5TCX8-2
	MAP3K21	ENST00000915953.1		c.673G>T	p.Gly225Cys	missense	Exon 1 of 10	ENSP00000586012.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000166 AC: 2 AN: 1206266 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 591498

African (AFR) AF: 0.00 AC: 0 AN: 23756

American (AMR) AF: 0.00 AC: 0 AN: 16358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18520

East Asian (EAS) AF: 0.00 AC: 0 AN: 25128

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3506

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 980222

Other (OTH) AF: 0.00 AC: 0 AN: 47736

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.055	D
PhyloP100		0.59
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.20
MutPred		0.50		Gain of catalytic residue at P224 (P = 0.0342)
MVP		0.76
MPC		2.8
ClinPred		0.71	D
GERP RS		0.51
Varity_R		0.29
gMVP		0.48
Mutation Taster		=87/13	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;