Genetic Variant MAP3K7CL:p.Glu14Gln (chr21-29085900-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020152.4(MAP3K7CL):c.40G>C(p.Glu14Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. E14K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MAP3K7CL
NM_020152.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.246

Publications

1 publications found

Variant links:

Genes affected

MAP3K7CL (HGNC:16457): (MAP3K7 C-terminal like) Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MAP3K7CL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0672259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
MAP3K7CL	NM_001286634.2 link	c.40G>C	p.Glu14Gln	missense_variant	Exon 2 of 8	NP_001273563.1	P57077-1B0EVZ6
MAP3K7CL	NM_001371369.1 link	c.40G>C	p.Glu14Gln	missense_variant	Exon 3 of 9	NP_001358298.1
MAP3K7CL	NM_020152.4 link	c.40G>C	p.Glu14Gln	missense_variant	Exon 4 of 10	NP_064537.1	P57077-1B0EVZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
MAP3K7CL	ENST00000341618.8 link	c.40G>C	p.Glu14Gln	missense_variant	Exon 2 of 8	1	ENSP00000343212.4	P57077-1
MAP3K7CL	ENST00000399947.6 link	c.40G>C	p.Glu14Gln	missense_variant	Exon 3 of 9	1	ENSP00000382828.2	P57077-1
MAP3K7CL	ENST00000496779.5 link	n.488G>C		non_coding_transcript_exon_variant	Exon 3 of 7	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251496

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.40G>C (p.E14Q) alteration is located in exon 3 (coding exon 1) of the MAP3K7CL gene. This alteration results from a G to C substitution at nucleotide position 40, causing the glutamic acid (E) at amino acid position 14 to be replaced by a glutamine (Q). 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

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.44

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0050

.;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.37

T;.;.;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.067

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N;N;N

PhyloP100

-0.25

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.0

D;N;N;N

REVEL

Benign

0.0090

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D

Polyphen

0.18

.;B;B;B

Vest4

0.072, 0.061

MutPred

0.19

Loss of ubiquitination at K19 (P = 0.0613);Loss of ubiquitination at K19 (P = 0.0613);Loss of ubiquitination at K19 (P = 0.0613);Loss of ubiquitination at K19 (P = 0.0613);

MVP

0.12

MPC

0.74

ClinPred

0.11

GERP RS

0.69

PromoterAI

-0.046

Neutral

(source)

Varity_R

0.074

gMVP

0.065

Mutation Taster

=293/7

polymorphism

(source)

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

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21-29085900-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over