22-38202227-A-G

Variant names:

• chr22-38202227-A-G
• rs2267372
• NM_012323.4:c.-32+15A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001161572.2(MAFF):​c.-43A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 152,292 control chromosomes in the GnomAD database, including 26,912 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.59 (26879 hom., cov: 34)
  • Exomes 𝑓: 0.55 (33 hom.)
• Consequence: MAFF NM_001161572.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.763
• Publications: 13 publications found

Genes affected

MAFF (HGNC:6780): (MAF bZIP transcription factor F) The protein encoded by this gene is a basic leucine zipper (bZIP) transcription factor that lacks a transactivation domain. It is known to bind the US-2 DNA element in the promoter of the oxytocin receptor (OTR) gene and most likely heterodimerizes with other leucine zipper-containing proteins to enhance expression of the OTR gene during term pregnancy. The encoded protein can also form homodimers, and since it lacks a transactivation domain, the homodimer may act as a repressor of transcription. This gene may also be involved in the cellular stress response. Multiple transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

PLA2G6 (HGNC:9039): (phospholipase A2 group VI) The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date. [provided by RefSeq, Dec 2010]

PLA2G6 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• neurodegeneration with brain iron accumulation 2B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• PLA2G6-associated neurodegeneration

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive Parkinson disease 14

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ENSG00000298301 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161572.2. 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
	MAFF	NM_012323.4	MANE Select	c.-32+15A>G		intron	N/A	NP_036455.1	Q9ULX9-1
	MAFF	NM_001161572.2		c.-43A>G		5_prime_UTR	Exon 1 of 3	NP_001155044.1	Q9ULX9-1
	MAFF	NM_001161574.2		c.-52+15A>G		intron	N/A	NP_001155046.1	Q9ULX9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAFF	ENST00000338483.7	TSL:1 MANE Select	c.-32+15A>G		intron	N/A	ENSP00000345393.2	Q9ULX9-1
	MAFF	ENST00000538320.5	TSL:4	c.-43A>G		5_prime_UTR	Exon 1 of 3	ENSP00000442060.1	Q9ULX9-1
	PLA2G6	ENST00000660610.1		c.-42+12226T>C		intron	N/A	ENSP00000499555.1	O60733-1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 90009 AN: 151938 Hom.: 26887 Cov.: 34

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.550 AC: 132 AN: 240 Hom.: 33 Cov.: 0 AF XY: 0.556 AC XY: 99 AN XY: 178

African (AFR) AF: 0.600 AC: 6 AN: 10

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 2 AN: 6

East Asian (EAS) AF: 0.667 AC: 8 AN: 12

South Asian (SAS) AF: 0.500 AC: 4 AN: 8

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.522 AC: 97 AN: 186

Other (OTH) AF: 0.813 AC: 13 AN: 16

GnomAD4 genome AF: 0.592 AC: 90041 AN: 152052 Hom.: 26879 Cov.: 34 AF XY: 0.588 AC XY: 43676 AN XY: 74320

African (AFR) AF: 0.595 AC: 24721 AN: 41532

American (AMR) AF: 0.538 AC: 8222 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2054 AN: 3464

East Asian (EAS) AF: 0.744 AC: 3825 AN: 5140

South Asian (SAS) AF: 0.458 AC: 2213 AN: 4828

European-Finnish (FIN) AF: 0.612 AC: 6472 AN: 10574

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.600 AC: 40767 AN: 67918

Other (OTH) AF: 0.595 AC: 1260 AN: 2116

Alfa AF: 0.596 Hom.: 4206

Bravo AF: 0.590

Asia WGS AF: 0.561 AC: 1942 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.3
DANN	Benign	0.59
PhyloP100		-0.76
PromoterAI		0.099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2267372; hg19: chr22-38598234;