14-70730628-T-A

Position:

• chr14-70730628-T-A

Variant summary

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

The ENST00000554752.7(MAP3K9):​c.3067A>T​(p.Ser1023Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. S1023T) 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: 7.64

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 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=0.21335402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K9	NM_001284230.2	c.3067A>T	p.Ser1023Cys	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.3067A>T	p.Ser1023Cys	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

May 09, 2022

The c.3109A>T (p.S1037C) alteration is located in exon 13 (coding exon 13) of the MAP3K9 gene. This alteration results from a A to T substitution at nucleotide position 3109, causing the serine (S) at amino acid position 1037 to be replaced by a cysteine (C). 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	0.14
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T;.;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.6	.;L;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	.;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.033	.;D;D;T;D;T
Sift4G	Benign	0.081	T;T;T;T;T;T
Polyphen		0.98, 1.0, 0.077, 0.0060	.;D;D;B;.;B
Vest4		0.34
MutPred		0.21		.;Loss of phosphorylation at S1023 (P = 0.0178);.;.;.;.;
MVP		0.69
MPC		0.98
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.35

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: chr14-71197345;