14-70730520-G-A

Position:

• chr14-70730520-G-A

Variant summary

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

The ENST00000554752.7(MAP3K9):​c.3175C>T​(p.Pro1059Ser) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1059L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K9 ENST00000554752.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.809

Genes affected

MAP3K9 (HGNC:6861): (mitogen-activated protein kinase kinase kinase 9) Enables protein serine/threonine kinase activity. Involved in protein autophosphorylation. [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=0.05407256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K9	NM_001284230.2	c.3175C>T	p.Pro1059Ser	missense_variant	12/12	ENST00000554752.7	NP_001271159.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K9	ENST00000554752.7	c.3175C>T	p.Pro1059Ser	missense_variant	12/12	1	NM_001284230.2	ENSP00000451612	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 10, 2024

The c.3217C>T (p.P1073S) alteration is located in exon 13 (coding exon 13) of the MAP3K9 gene. This alteration results from a C to T substitution at nucleotide position 3217, causing the proline (P) at amino acid position 1073 to be replaced by a serine (S). 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	0.063
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.72
DEOGEN2	Benign	0.030	T;T;.;T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.054	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.46	.;N;.;.;.;.
MutationTaster	Benign	0.69	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.81	.;N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.77	.;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T
Polyphen		0.0050, 0.0, 0.0010, 0.017	.;B;B;B;.;B
Vest4		0.050
MutPred		0.18		.;Gain of phosphorylation at P1059 (P = 0.0528);.;.;.;.;
MVP		0.35
MPC		0.29
ClinPred		0.025	T
GERP RS		1.2
Varity_R		0.017
gMVP		0.40

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: chr14-71197237;