5-56815617-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_005921.2(MAP3K1):c.44C>G(p.Pro15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,312,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P15P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.56

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25606436).
• BP6: Variant 5-56815617-C-G is Benign according to our data. Variant chr5-56815617-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1033045.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.44C>G	p.Pro15Arg	missense_variant	1/20	ENST00000399503.4
MAP3K1	XM_047417218.1	c.44C>G	p.Pro15Arg	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.44C>G	p.Pro15Arg	missense_variant	1/20	1	NM_005921.2	P1

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000426 AC: 1 AN: 23490 Hom.: 0 AF XY: 0.0000681 AC XY: 1 AN XY: 14684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.000120 AC: 139 AN: 1160900 Hom.: 0 Cov.: 31 AF XY: 0.000126 AC XY: 71 AN XY: 563282

Gnomad4 AFR exome AF: 0.0000848

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000372

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.0000403

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.0000862

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151212 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 73862

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000309 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

46,XY sex reversal 6 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.44C>G (p.P15R) alteration is located in exon 1 (coding exon 1) of the MAP3K1 gene. This alteration results from a C to G substitution at nucleotide position 44, causing the proline (P) at amino acid position 15 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.89	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.10
Sift	Uncertain	0.014	D
Sift4G	Benign	0.10	T
Polyphen		0.93	P
Vest4		0.59
MutPred		0.31		Gain of MoRF binding (P = 9e-04);
MVP		0.57
MPC		0.79
ClinPred		0.22	T
GERP RS		3.1
Varity_R		0.22
gMVP		0.15

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: rs765282250; hg19: chr5-56111444;