22-38204535-C-T

Variant names:

• chr22-38204535-C-T
• rs2267373
• NM_012323.4:c.-32+2323C>T

Variant summary

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

The NM_012323.4(MAFF):​c.-32+2323C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 151,906 control chromosomes in the GnomAD database, including 25,875 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 0.58 (25875 hom., cov: 31)
• Consequence: MAFF NM_012323.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.216
• Publications: 24 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, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012323.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAFF	NM_012323.4	MANE Select	c.-32+2323C>T		intron	N/A	NP_036455.1
	MAFF	NM_001161572.2		c.-32+2297C>T		intron	N/A	NP_001155044.1
	MAFF	NM_001161573.1		c.-32+1451C>T		intron	N/A	NP_001155045.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAFF	ENST00000338483.7	TSL:1 MANE Select	c.-32+2323C>T		intron	N/A	ENSP00000345393.2
	PLA2G6	ENST00000660610.1		c.-42+9918G>A		intron	N/A	ENSP00000499555.1
	MAFF	ENST00000417948.6	TSL:4	c.-32+1451C>T		intron	N/A	ENSP00000416493.2

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88245 AN: 151788 Hom.: 25881 Cov.: 31

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.586

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.581 AC: 88285 AN: 151906 Hom.: 25875 Cov.: 31 AF XY: 0.577 AC XY: 42803 AN XY: 74234

African (AFR) AF: 0.609 AC: 25223 AN: 41406

American (AMR) AF: 0.531 AC: 8102 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1988 AN: 3472

East Asian (EAS) AF: 0.642 AC: 3306 AN: 5146

South Asian (SAS) AF: 0.399 AC: 1924 AN: 4818

European-Finnish (FIN) AF: 0.604 AC: 6375 AN: 10554

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

European-Non Finnish (NFE) AF: 0.583 AC: 39631 AN: 67938

Other (OTH) AF: 0.581 AC: 1225 AN: 2110

Alfa AF: 0.581 Hom.: 68737

Bravo AF: 0.580

Asia WGS AF: 0.490 AC: 1703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2267373; hg19: chr22-38600542;