20-40688642-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_005461.5(MAFB):​c.209C>T​(p.Ser70Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S70A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MAFB
NM_005461.5 missense

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.81
Variant links:
Genes affected
MAFB (HGNC:6408): (MAF bZIP transcription factor B) The protein encoded by this gene is a basic leucine zipper (bZIP) transcription factor that plays an important role in the regulation of lineage-specific hematopoiesis. The encoded nuclear protein represses ETS1-mediated transcription of erythroid-specific genes in myeloid cells. This gene contains no introns. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a region_of_interest Disordered (size 44) in uniprot entity MAFB_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_005461.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-40688643-A-C is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.882
PP5
Variant 20-40688642-G-A is Pathogenic according to our data. Variant chr20-40688642-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30770.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-40688642-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAFBNM_005461.5 linkc.209C>T p.Ser70Leu missense_variant 1/1 ENST00000373313.3 NP_005452.2 Q9Y5Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAFBENST00000373313.3 linkc.209C>T p.Ser70Leu missense_variant 1/16 NM_005461.5 ENSP00000362410.2 Q9Y5Q3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 06, 2019- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 12, 2024This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 70 of the MAFB protein (p.Ser70Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multicentric carpotarsal osteolysis syndrome (PMID: 22387013). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30770). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAFB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Multicentric carpo-tarsal osteolysis with or without nephropathy Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 09, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-4.4
D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.78
MutPred
0.27
Loss of glycosylation at S70 (P = 0.0038);
MVP
0.98
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.47
gMVP
0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387907006; hg19: chr20-39317282; API