rs387907004

Variant names:

• chr20-40688667-T-C
• rs387907004
• NM_005461.5:c.184A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-40688667-T-C
• chr20-40688667-T-G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_005461.5(MAFB):​c.184A>G​(p.Thr62Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T62P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAFB NM_005461.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.09
• Publications: 5 publications found

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]

MAFB Gene-Disease associations (from GenCC):

• multicentric carpo-tarsal osteolysis with or without nephropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Duane retraction syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• Duane retraction syndrome 3 with or without deafness

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr20-40688667-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30768.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 20-40688667-T-C is Pathogenic according to our data. Variant chr20-40688667-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 807627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFB	NM_005461.5	c.184A>G	p.Thr62Ala	missense_variant	Exon 1 of 1	ENST00000373313.3	NP_005452.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAFB	ENST00000373313.3	c.184A>G	p.Thr62Ala	missense_variant	Exon 1 of 1	6	NM_005461.5	ENSP00000362410.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 16, 2020

Department of Hand Surgery, Beijing Jishuitan Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ZANKL A et al. reported missense mutations clustering in the Amino-terminal transcriptional activation domain of MAFB in 11 unrelated simplex cases and in two families with Multicentric Carpotarsal Osteolysis in 2012. A patient had the variant c.184A>C (same site as the variant we found), causing the amino acid substitution p.Thr62Pro. The same variant was previously submitted to Clinvar (SCV001150154.1), the patient in that record also had MCTO. -

Jan 25, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Polyphen		0.81	P
Vest4		0.49
MutPred		0.13		Loss of glycosylation at T62 (P = 0.0065);
MVP		0.89
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.47
gMVP		0.88
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs387907004; hg19: chr20-39317307;