rs1145728

Variant names:

• chr6-90544033-A-T
• rs1145728
• NM_145331.3:c.1291+519T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145331.3(MAP3K7):​c.1291+519T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 151,960 control chromosomes in the GnomAD database, including 3,988 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3988 hom., cov: 32)
• Consequence: MAP3K7 NM_145331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0190
• Publications: 7 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• frontometaphyseal dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina
• frontometaphyseal dysplasia 2

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K7	NM_145331.3	c.1291+519T>A		intron_variant	Intron 12 of 16	ENST00000369329.8	NP_663304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K7	ENST00000369329.8	c.1291+519T>A		intron_variant	Intron 12 of 16	1	NM_145331.3	ENSP00000358335.3

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31822 AN: 151842 Hom.: 3990 Cov.: 32

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0973

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.217

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.209 AC: 31816 AN: 151960 Hom.: 3988 Cov.: 32 AF XY: 0.209 AC XY: 15492 AN XY: 74236

African (AFR) AF: 0.0861 AC: 3575 AN: 41508

American (AMR) AF: 0.168 AC: 2553 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 861 AN: 3466

East Asian (EAS) AF: 0.0977 AC: 502 AN: 5138

South Asian (SAS) AF: 0.133 AC: 642 AN: 4822

European-Finnish (FIN) AF: 0.323 AC: 3414 AN: 10562

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19494 AN: 67916

Other (OTH) AF: 0.218 AC: 460 AN: 2110

Alfa AF: 0.253 Hom.: 676

Bravo AF: 0.193

Asia WGS AF: 0.152 AC: 527 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.82
PhyloP100		0.019
Mutation Taster		=100/0	polymorphism (auto)

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: rs1145728; hg19: chr6-91253752; COSMIC: COSV65225869;