rs1554035648

Positions:

• chr5-56881194-T-A
• chr5-56881194-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_005921.2(MAP3K1):​c.2291T>A​(p.Leu764Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L764R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.52

Genes affected

MAP3K1 (HGNC:6848): (mitogen-activated protein kinase kinase kinase 1) The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-56881194-T-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K1	NM_005921.2	c.2291T>A	p.Leu764Gln	missense_variant	13/20	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.2291T>A	p.Leu764Gln	missense_variant	13/18		XP_047273174.1
MAP3K1	XM_047417219.1	c.1880T>A	p.Leu627Gln	missense_variant	14/21		XP_047273175.1
MAP3K1	XM_047417220.1	c.1880T>A	p.Leu627Gln	missense_variant	14/21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.2291T>A	p.Leu764Gln	missense_variant	13/20	1	NM_005921.2	ENSP00000382423.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.42		Loss of stability (P = 8e-04);
MVP		0.90
MPC		0.67
ClinPred		0.81	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.79

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: chr5-56177021;