NM_145331.3:c.*1085G>A

Variant names:

• chr6-90515416-C-T
• rs157705
• NM_145331.3:c.*1085G>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.906
• Publications: 11 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MAP3K7 NM_145331.3	MANE Select	c.*1085G>A	3_prime_UTR	Exon 17 of 17	Prot: NP_663304.1 UniProt:
	MAP3K7 NM_003188.4		c.*1085G>A	3_prime_UTR	Exon 16 of 16	Prot: NP_003179.1 UniProt:
	MAP3K7 NM_145332.3		c.*1233G>A	3_prime_UTR	Exon 16 of 16	Prot: NP_663305.1 UniProt:

MAP3K7 NM_145331.3

MANE Select

HGVSc / HGVSpc.*1085G>A

Exon rankExon 17 of 17

3_prime_UTR

Prot: NP_663304.1UniProt: O43318-1

MAP3K7 NM_003188.4

HGVSc / HGVSpc.*1085G>A

Exon rankExon 16 of 16

3_prime_UTR

Prot: NP_003179.1UniProt: O43318-2

MAP3K7 NM_145332.3

HGVSc / HGVSpc.*1233G>A

Exon rankExon 16 of 16

3_prime_UTR

Prot: NP_663305.1UniProt: O43318-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MAP3K7 ENST00000369329.8	TSL:1MANE Select	c.*1085G>A	3_prime_UTR	Exon 17 of 17	Prot: ENSP00000358335.3 UniProt:
	MAP3K7 ENST00000369332.7	TSL:1	c.*1085G>A	3_prime_UTR	Exon 16 of 16	Prot: ENSP00000358338.3 UniProt:
	MAP3K7 ENST00000369325.7	TSL:1	c.*1233G>A	3_prime_UTR	Exon 16 of 16	Prot: ENSP00000358331.3 UniProt:

MAP3K7 ENST00000369329.8

TSL:1MANE Select

HGVSc / HGVSpc.*1085G>A

Exon rankExon 17 of 17

3_prime_UTR

Prot: ENSP00000358335.3UniProt: O43318-1

MAP3K7 ENST00000369332.7

TSL:1

HGVSc / HGVSpc.*1085G>A

Exon rankExon 16 of 16

3_prime_UTR

Prot: ENSP00000358338.3UniProt: O43318-2

MAP3K7 ENST00000369325.7

TSL:1

HGVSc / HGVSpc.*1233G>A

Exon rankExon 16 of 16

3_prime_UTR

Prot: ENSP00000358331.3UniProt: O43318-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.357	AC:54134	Hom:10024	AN:151534	Cov:32
GnomAD4 exome Warning	AF:	AC:0	Hom:0	AN:0	Cov:0
GnomAD4 genome	AF: 0.357	AC:54190	Hom:10033	AN:151652	Cov:32
TOPMed (Bravo)	AF: 0.365	AC:96649	Hom:18063	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.335	AC:77426	Hom:13174	AN:231070	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.335	AC:784	Hom:131	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.314	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.397	AC:119	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.355	AC:1235	Hom:	AN:3466	Cov:
Korea4K (4,157 Koreans)	AF: 0.320	AC:2310	Hom:	AN:7210	Cov:
Qatari Genome	AF: 0.392	AC:69	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.336	AC:40898	Hom:6869	AN:121788	Cov:
Turkish Variome	AF: 0.354	AC:547	Hom:99	AN:1546	Cov:
UK10K	AF: 0.322	AC:2434	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.307	AC:2755	Hom:424	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.179	4050	22656	0.0863	2518	29164

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.5
DANN	Benign	0.71
GPN-Star LLR	N/A	-0.58
GPN-Star score	N/A	0.58
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.91

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs157705;

hg19: chr6-91225135;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar