1-233382679-A-G

Variant names:

• chr1-233382679-A-G
• rs1663941517
• NM_032435.3:c.3079A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032435.3(MAP3K21):​c.3079A>G​(p.Ile1027Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAP3K21 NM_032435.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03219357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K21	NM_032435.3	c.3079A>G	p.Ile1027Val	missense_variant	Exon 10 of 10	ENST00000366624.8	NP_115811.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K21	ENST00000366624.8	c.3079A>G	p.Ile1027Val	missense_variant	Exon 10 of 10	1	NM_032435.3	ENSP00000355583.3
MAP3K21	ENST00000366622.1	c.1417A>G	p.Ile473Val	missense_variant	Exon 4 of 4	1		ENSP00000355581.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461350 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726880

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3079A>G (p.I1027V) alteration is located in exon 10 (coding exon 10) of the KIAA1804 gene. This alteration results from a A to G substitution at nucleotide position 3079, causing the isoleucine (I) at amino acid position 1027 to be replaced by a valine (V). 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	0.070
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.0
DANN	Benign	0.52
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0060	B;.
Vest4		0.017
MutPred		0.28		Loss of helix (P = 0.0167);.;
MVP		0.17
MPC		0.091
ClinPred		0.12	T
GERP RS		2.4
Varity_R		0.016
gMVP		0.086

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: rs1663941517; hg19: chr1-233518425;