Genetic Variant NM_001006617.3:c.673G>A (chr9-125559808-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001006617.3(MAPKAP1):c.673G>A(p.Asp225Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MAPKAP1
NM_001006617.3 missense, splice_region

Scores

Splicing: ADA: 0.9800

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.54

Publications

0 publications found

Variant links:

Genes affected

MAPKAP1 (HGNC:18752): (MAPK associated protein 1) This gene encodes a protein that is highly similar to the yeast SIN1 protein, a stress-activated protein kinase. Alternatively spliced transcript variants encoding distinct isoforms have been described. Alternate polyadenylation sites as well as alternate 3' UTRs have been identified for transcripts of this gene. [provided by RefSeq, Jul 2008]

MAPKAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006617.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPKAP1	NM_001006617.3	MANE Select	c.673G>A	p.Asp225Asn	missense splice_region	Exon 6 of 12	NP_001006618.1	Q9BPZ7-1
MAPKAP1	NM_024117.4		c.673G>A	p.Asp225Asn	missense splice_region	Exon 6 of 11	NP_077022.1	Q9BPZ7-2
MAPKAP1	NM_001006619.2		c.673G>A	p.Asp225Asn	missense splice_region	Exon 6 of 11	NP_001006620.1	Q9BPZ7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPKAP1	ENST00000265960.8	TSL:1 MANE Select	c.673G>A	p.Asp225Asn	missense splice_region	Exon 6 of 12	ENSP00000265960.3	Q9BPZ7-1
MAPKAP1	ENST00000350766.7	TSL:1	c.673G>A	p.Asp225Asn	missense splice_region	Exon 6 of 11	ENSP00000265961.5	Q9BPZ7-2
MAPKAP1	ENST00000373511.6	TSL:1	c.673G>A	p.Asp225Asn	missense splice_region	Exon 6 of 11	ENSP00000362610.2	Q9BPZ7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

44246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25880

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

85568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108086

Other (OTH)

AF:

0.00

AC:

AN:

60140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.081

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0037

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.57

PhyloP100

7.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.0

REVEL

Benign

0.22

Sift

Uncertain

0.013

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.30

MutPred

0.64

Gain of methylation at K222 (P = 0.1046)

MVP

0.24

MPC

0.74

ClinPred

0.91

GERP RS

5.8

Varity_R

0.11

gMVP

0.43

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.81

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over