1-233328708-G-C

Variant names:

• chr1-233328708-G-C
• NM_032435.3:c.680G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032435.3(MAP3K21):​c.680G>C​(p.Arg227Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP3K21 NM_032435.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K21	NM_032435.3	c.680G>C	p.Arg227Pro	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.680G>C	p.Arg227Pro	missense_variant	Exon 1 of 10	1	NM_032435.3	ENSP00000355583.3
MAP3K21	ENST00000366623.7	c.680G>C	p.Arg227Pro	missense_variant	Exon 1 of 6	1		ENSP00000355582.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000117 AC: 14 AN: 1191998 Hom.: 0 Cov.: 31 AF XY: 0.00000854 AC XY: 5 AN XY: 585236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000873

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000826

Gnomad4 OTH exome AF: 0.0000216

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.680G>C (p.R227P) alteration is located in exon 1 (coding exon 1) of the KIAA1804 gene. This alteration results from a G to C substitution at nucleotide position 680, causing the arginine (R) at amino acid position 227 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	.;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.51	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.22	T;D
Polyphen		1.0	D;D
Vest4		0.39
MutPred		0.52		Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);
MVP		0.63
MPC		3.4
ClinPred		0.79	D
GERP RS		3.6
Varity_R		0.40
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-233464454; COSMIC: COSV105922205;