21-29085901-A-C

Variant names:

• chr21-29085901-A-C
• ENST00000341618.8:c.41A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020152.4(MAP3K7CL):​c.41A>C​(p.Glu14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: MAP3K7CL NM_020152.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.322
• Publications: 0 publications found

Genes affected

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

ACMG classification

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=0.061489284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K7CL	NM_001286634.2	c.41A>C	p.Glu14Ala	missense_variant	Exon 2 of 8		NP_001273563.1
MAP3K7CL	NM_001371369.1	c.41A>C	p.Glu14Ala	missense_variant	Exon 3 of 9		NP_001358298.1
MAP3K7CL	NM_020152.4	c.41A>C	p.Glu14Ala	missense_variant	Exon 4 of 10		NP_064537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K7CL	ENST00000341618.8	c.41A>C	p.Glu14Ala	missense_variant	Exon 2 of 8	1		ENSP00000343212.4
MAP3K7CL	ENST00000399947.6	c.41A>C	p.Glu14Ala	missense_variant	Exon 3 of 9	1		ENSP00000382828.2
MAP3K7CL	ENST00000496779.5	n.489A>C		non_coding_transcript_exon_variant	Exon 3 of 7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41A>C (p.E14A) alteration is located in exon 3 (coding exon 1) of the MAP3K7CL gene. This alteration results from a A to C substitution at nucleotide position 41, causing the glutamic acid (E) at amino acid position 14 to be replaced by an alanine (A). 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	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0059	.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.37	T;.;.;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;N;N
PhyloP100		0.32
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-6.0	D;N;N;D
REVEL	Benign	0.028
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		0.015	.;B;B;B
Vest4		0.19, 0.15
MutPred		0.24		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		0.072
MPC		0.58
ClinPred		0.15	T
GERP RS		0.95
PromoterAI		0.012	Neutral
Varity_R		0.045
gMVP		0.084
Mutation Taster		=296/4	polymorphism

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

Other links and lift over

hg19: chr21-30458222;