chr21-29085901-A-C

Position:

• chr21-29085901-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000341618.8(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. 13/20 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 ENST00000341618.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.322

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	UniProt
MAP3K7CL	NM_001286634.2	c.41A>C	p.Glu14Ala	missense_variant	2/8
MAP3K7CL	NM_001371369.1	c.41A>C	p.Glu14Ala	missense_variant	3/9
MAP3K7CL	NM_020152.4	c.41A>C	p.Glu14Ala	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K7CL	ENST00000341618.8	c.41A>C	p.Glu14Ala	missense_variant	2/8	1
MAP3K7CL	ENST00000399947.6	c.41A>C	p.Glu14Ala	missense_variant	3/9	1
MAP3K7CL	ENST00000496779.5	n.489A>C		non_coding_transcript_exon_variant	3/7	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

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
MutationTaster	Benign	1.0	N;N;N;N;N;N
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
Varity_R		0.045
gMVP		0.084

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: chr21-30458222;