4-1315477-C-A

Variant names:

• chr4-1315477-C-A
• rs74997573
• NM_001017405.3:c.333C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001017405.3(MAEA):​c.333C>A​(p.Ser111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S111S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAEA NM_001017405.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0730
• Publications: 0 publications found

Genes affected

MAEA (HGNC:13731): (macrophage erythroblast attacher, E3 ubiquitin ligase) This gene encodes a protein that mediates the attachment of erythroblasts to macrophages. This attachment promotes terminal maturation and enucleation of erythroblasts, presumably by suppressing apoptosis. The encoded protein is an integral membrane protein with the N-terminus on the extracellular side and the C-terminus on the cytoplasmic side of the cell. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29122692).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017405.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAEA	NM_001017405.3	MANE Select	c.333C>A	p.Ser111Arg	missense	Exon 3 of 9	NP_001017405.1	Q7L5Y9-1
	MAEA	NM_001297432.2		c.330C>A	p.Ser110Arg	missense	Exon 3 of 9	NP_001284361.1	B4DVN3
	MAEA	NM_005882.5		c.333C>A	p.Ser111Arg	missense	Exon 3 of 8	NP_005873.2	Q7L5Y9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAEA	ENST00000303400.9	TSL:1 MANE Select	c.333C>A	p.Ser111Arg	missense	Exon 3 of 9	ENSP00000302830.4	Q7L5Y9-1
	MAEA	ENST00000503693.1	TSL:1	n.339C>A		non_coding_transcript_exon	Exon 3 of 5
	MAEA	ENST00000509531.5	TSL:1	n.333C>A		non_coding_transcript_exon	Exon 3 of 7	ENSP00000426966.1	D6RDW4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461570 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.073
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.28
Sift	Uncertain	0.014	D
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.61
MutPred		0.36		Gain of MoRF binding (P = 0.0064)
MVP		0.34
MPC		1.4
ClinPred		0.99	D
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.86
Mutation Taster		=49/51	disease causing

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: rs74997573; hg19: chr4-1309265;