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GeneBe

5-56815588-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_005921.2(MAP3K1):c.15G>A(p.Ala5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,296,296 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 9 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

MAP3K1
NM_005921.2 synonymous

Scores

1
1

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.27
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-56815588-G-A is Benign according to our data. Variant chr5-56815588-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1612863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=2.27 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 383 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAP3K1NM_005921.2 linkuse as main transcriptc.15G>A p.Ala5= synonymous_variant 1/20 ENST00000399503.4
MAP3K1XM_047417218.1 linkuse as main transcriptc.15G>A p.Ala5= synonymous_variant 1/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAP3K1ENST00000399503.4 linkuse as main transcriptc.15G>A p.Ala5= synonymous_variant 1/201 NM_005921.2 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00254
AC:
383
AN:
150850
Hom.:
9
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000317
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000198
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00208
Gnomad FIN
AF:
0.0247
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00143
Gnomad OTH
AF:
0.00145
GnomAD3 exomes
AF:
0.00141
AC:
11
AN:
7816
Hom.:
0
AF XY:
0.00140
AC XY:
7
AN XY:
4998
show subpopulations
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:
0.000948
Gnomad FIN exome
AF:
0.0119
Gnomad NFE exome
AF:
0.00104
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00165
AC:
1889
AN:
1145334
Hom.:
4
Cov.:
31
AF XY:
0.00165
AC XY:
914
AN XY:
553586
show subpopulations
Gnomad4 AFR exome
AF:
0.000215
Gnomad4 AMR exome
AF:
0.000100
Gnomad4 ASJ exome
AF:
0.000579
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000842
Gnomad4 FIN exome
AF:
0.0177
Gnomad4 NFE exome
AF:
0.00142
Gnomad4 OTH exome
AF:
0.00127
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00254
AC:
383
AN:
150962
Hom.:
9
Cov.:
33
AF XY:
0.00320
AC XY:
236
AN XY:
73778
show subpopulations
Gnomad4 AFR
AF:
0.000316
Gnomad4 AMR
AF:
0.000198
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00208
Gnomad4 FIN
AF:
0.0247
Gnomad4 NFE
AF:
0.00143
Gnomad4 OTH
AF:
0.00143
Alfa
AF:
0.000954
Hom.:
0
Bravo
AF:
0.000608

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

46,XY sex reversal 6 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeNov 27, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023MAP3K1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
Cadd
Benign
17
Dann
Uncertain
0.98

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759046760; hg19: chr5-56111415; API