2-134983723-T-G

Position:

• chr2-134983723-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025052.5(MAP3K19):​c.3175A>C​(p.Ile1059Leu) 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. 16/21 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)
• Consequence: MAP3K19 NM_025052.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.153

Genes affected

MAP3K19 (HGNC:26249): (mitogen-activated protein kinase kinase kinase 19) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22721258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K19	NM_025052.5	c.3175A>C	p.Ile1059Leu	missense_variant	11/13	ENST00000392915.7	NP_079328.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K19	ENST00000392915.7	c.3175A>C	p.Ile1059Leu	missense_variant	11/13	5	NM_025052.5	ENSP00000376647.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.3175A>C (p.I1059L) alteration is located in exon 8 (coding exon 8) of the MAP3K19 gene. This alteration results from a A to C substitution at nucleotide position 3175, causing the isoleucine (I) at amino acid position 1059 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.0061	T;T;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	.;T;T;T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	L;L;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	.;N;N;N;N;N
REVEL	Benign	0.060
Sift	Uncertain	0.0060	.;D;D;D;T;T
Sift4G	Uncertain	0.0090	.;D;D;D;T;D
Polyphen		0.17	B;B;B;B;B;.
Vest4		0.52, 0.37, 0.34, 0.44
MutPred		0.31		Gain of catalytic residue at I1059 (P = 0.001);Gain of catalytic residue at I1059 (P = 0.001);.;.;.;.;
MVP		0.66
MPC		0.13
ClinPred		0.52	D
GERP RS		2.2
Varity_R		0.12
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr2-135741293;