chr6-90515416-C-T

Variant names:

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_145331.3(MAP3K7):c.*1085G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.357 (AC=54,190) in the gnomAD database across 151,652 control chromosomes, including 10,033 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.443. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.36 ( 10033 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

MAP3K7
NM_145331.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.906

Publications

11 publications found

Variant links:

Genes affected

MAP3K7 (HGNC:6859): (mitogen-activated protein kinase kinase kinase 7) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. In response to IL-1, this protein forms a kinase complex including TRAF6, MAP3K7P1/TAB1 and MAP3K7P2/TAB2; this complex is required for the activation of nuclear factor kappa B. This kinase can also activate MAPK8/JNK, MAP2K4/MKK4, and thus plays a role in the cell response to environmental stresses. Four alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

MAP3K7 Gene-Disease associations (from GenCC):

cardiospondylocarpofacial syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
frontometaphyseal dysplasia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina
frontometaphyseal dysplasia 2
Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

MAP3K7 links:

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new If you want to explore the variant's impact on the transcript NM_145331.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -12 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4429 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_145331.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP3K7	NM_145331.3	MANE Select	c.*1085G>A	3_prime_UTR	Exon 17 of 17	NP_663304.1	O43318-1
MAP3K7	NM_003188.4		c.*1085G>A	3_prime_UTR	Exon 16 of 16	NP_003179.1	O43318-2
MAP3K7	NM_145332.3		c.*1233G>A	3_prime_UTR	Exon 16 of 16	NP_663305.1	O43318-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP3K7	ENST00000369329.8	TSL:1 MANE Select	c.*1085G>A	3_prime_UTR	Exon 17 of 17	ENSP00000358335.3	O43318-1
MAP3K7	ENST00000369332.7	TSL:1	c.*1085G>A	3_prime_UTR	Exon 16 of 16	ENSP00000358338.3	O43318-2
MAP3K7	ENST00000369325.7	TSL:1	c.*1233G>A	3_prime_UTR	Exon 16 of 16	ENSP00000358331.3	O43318-3

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54134

AN:

151534

Hom.:

10024

Cov.:

show subpopulations

Gnomad AFR

AF:

0.449

Gnomad AMI

AF:

0.334

Gnomad AMR

AF:

0.346

Gnomad ASJ

AF:

0.468

Gnomad EAS

AF:

0.317

Gnomad SAS

AF:

0.423

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.315

Gnomad OTH

AF:

0.380

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.357

AC:

54190

AN:

151652

Hom.:

10033

Cov.:

AF XY:

0.353

AC XY:

26168

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.448

AC:

18550

AN:

41380

American (AMR)

AF:

0.347

AC:

5275

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.468

AC:

1621

AN:

3462

East Asian (EAS)

AF:

0.316

AC:

1631

AN:

5158

South Asian (SAS)

AF:

0.424

AC:

2041

AN:

4814

European-Finnish (FIN)

AF:

0.239

AC:

2523

AN:

10548

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.315

AC:

21314

AN:

67756

Other (OTH)

AF:

0.385

AC:

813

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1760

3519

5279

7038

8798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

528

1056

1584

2112

2640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.333

Hom.:

11765

Bravo

AF:

0.365

Asia WGS

AF:

0.355

AC:

1235

AN:

3466

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.336

AC:

40898

AN:

121788

Turkish Variome

AF:

0.354

AC:

547

AN:

1546

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.307

AC:

2755

AN:

8960

Hom.:

424

ABraOM SABE-WGS-1171

AF:

0.335

AC:

784

AN:

2342

Hom.:

131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

7.5

(source)

DANN

Benign

0.71

PhyloP100

0.91

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over