rs140644118

Variant names:

• chr21-29085900-G-A
• rs140644118
• ENST00000341618.8:c.40G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-29085900-G-A
• chr21-29085900-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020152.4(MAP3K7CL):​c.40G>A​(p.Glu14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. 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. E14A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: MAP3K7CL NM_020152.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.246
• Publications: 1 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077014565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K7CL	NM_001286634.2	c.40G>A	p.Glu14Lys	missense_variant	Exon 2 of 8		NP_001273563.1
MAP3K7CL	NM_001371369.1	c.40G>A	p.Glu14Lys	missense_variant	Exon 3 of 9		NP_001358298.1
MAP3K7CL	NM_020152.4	c.40G>A	p.Glu14Lys	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.40G>A	p.Glu14Lys	missense_variant	Exon 2 of 8	1		ENSP00000343212.4
MAP3K7CL	ENST00000399947.6	c.40G>A	p.Glu14Lys	missense_variant	Exon 3 of 9	1		ENSP00000382828.2
MAP3K7CL	ENST00000496779.5	n.488G>A		non_coding_transcript_exon_variant	Exon 3 of 7	1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000235 AC: 59 AN: 251496 AF XY: 0.000272

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

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: 0.000112 AC: 163 AN: 1461836 Hom.: 1 Cov.: 30 AF XY: 0.000155 AC XY: 113 AN XY: 727218

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00161 AC: 139 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111968

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74452

African (AFR) AF: 0.0000963 AC: 4 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000219 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40G>A (p.E14K) alteration is located in exon 3 (coding exon 1) of the MAP3K7CL gene. This alteration results from a G to A substitution at nucleotide position 40, causing the glutamic acid (E) at amino acid position 14 to be replaced by a lysine (K). 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	-0.49	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0052	.;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.47	T;.;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0077	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;N;N
PhyloP100		-0.25
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.0	D;N;N;N
REVEL	Benign	0.023
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		0.0010	.;B;B;B
Vest4		0.11, 0.086
MVP		0.12
MPC		0.61
ClinPred		0.073	T
GERP RS		0.69
PromoterAI		-0.026	Neutral
Varity_R		0.048
gMVP		0.12
Mutation Taster		=293/7	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

dbSNP: rs140644118; hg19: chr21-30458221; COSMIC: COSV99726745;