20-40688639-G-A

Position:

• chr20-40688639-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_005461.5(MAFB):​c.212C>T​(p.Pro71Leu) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P71S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAFB NM_005461.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.81

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 chr20-40688640-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30771.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 20-40688639-G-A is Pathogenic according to our data. Variant chr20-40688639-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30772.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-40688639-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAFB	NM_005461.5	c.212C>T	p.Pro71Leu	missense_variant	1/1	ENST00000373313.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAFB	ENST00000373313.3	c.212C>T	p.Pro71Leu	missense_variant	1/1		NM_005461.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Multicentric carpo-tarsal osteolysis with or without nephropathy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 07, 2020	The MAFB c.212C>T (p.Pro71Leu) variant is a missense variant and has been reported in at least two individuals in a de novo heterozygous state. Both individuals presented with skeletal anomalies characteristic of multicentric carpotarsal osteolysis syndrome, with one individual also presenting with renal disease (Zankl et al. 2012; Park et al. 2018). While there are no functional studies for this variant, it is located in the amino-terminal transcriptional activation domain where all clinically significant variants identified to date are located, specifically across residues 54-71. In addition, different amino acid changes at the Pro71 residue have been reported in affected individuals (Zankl et al. 2012; Mumm et al. 2014). The p.Pro71Leu variant was absent from 164 control individuals (Zankl et al. 2012) and is not reported in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the collective evidence, the p.Pro71Leu variant is classified as pathogenic for multicentric carpotarsal osteolysis syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.27		Loss of glycosylation at P71 (P = 0.0153);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.78
gMVP		0.92

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

Other links and lift over

dbSNP: rs387907008; hg19: chr20-39317279;