22-38214762-C-A

Variant names:

• chr22-38214762-C-A
• rs933865522
• NM_012323.4:c.379C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012323.4(MAFF):​c.379C>A​(p.Pro127Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000787 in 1,269,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P127S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: MAFF NM_012323.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17342678).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAFF	NM_012323.4	MANE Select	c.379C>A	p.Pro127Thr	missense	Exon 3 of 3	NP_036455.1	Q9ULX9-1
	MAFF	NM_001161572.2		c.379C>A	p.Pro127Thr	missense	Exon 3 of 3	NP_001155044.1	Q9ULX9-1
	MAFF	NM_001161573.1		c.379C>A	p.Pro127Thr	missense	Exon 3 of 3	NP_001155045.1	Q9ULX9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAFF	ENST00000338483.7	TSL:1 MANE Select	c.379C>A	p.Pro127Thr	missense	Exon 3 of 3	ENSP00000345393.2	Q9ULX9-1
	MAFF	ENST00000407965.2	TSL:2	c.379C>A	p.Pro127Thr	missense	Exon 3 of 3	ENSP00000384094.1
	MAFF	ENST00000417948.6	TSL:4	c.379C>A	p.Pro127Thr	missense	Exon 3 of 3	ENSP00000416493.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.87e-7 AC: 1 AN: 1269918 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 625014

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24620

American (AMR) AF: 0.00 AC: 0 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19576

East Asian (EAS) AF: 0.00 AC: 0 AN: 27498

South Asian (SAS) AF: 0.00 AC: 0 AN: 63854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5074

European-Non Finnish (NFE) AF: 9.73e-7 AC: 1 AN: 1027246

Other (OTH) AF: 0.00 AC: 0 AN: 52248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.78
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.29	N
PhyloP100		1.5
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.15
Sift	Benign	0.031	D
Sift4G	Uncertain	0.015	D
Polyphen		0.0010	B
Vest4		0.038
MutPred		0.35		Gain of loop (P = 0.0097)
MVP		0.96
MPC		1.5
ClinPred		0.26	T
GERP RS		1.7
PromoterAI		-0.14	Neutral
Varity_R		0.084
gMVP		0.45
Mutation Taster		=87/13	polymorphism

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: rs933865522; hg19: chr22-38610769;