22-38201370-G-C

Variant names:

• chr22-38201370-G-C
• rs4374456
• ENST00000624676.1:n.604G>C

Variant summary

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

The ENST00000624676.1(MAFF):​n.604G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,770 control chromosomes in the GnomAD database, including 20,422 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 0.52 (20411 hom., cov: 31)
  • Exomes 𝑓: 0.44 (11 hom.)
• Consequence: MAFF ENST00000624676.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.346
• Publications: 4 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

ENSG00000298301 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAFF	ENST00000624676.1	n.604G>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
PLA2G6	ENST00000660610.1	c.-42+13083C>G		intron_variant	Intron 1 of 16			ENSP00000499555.1
PLA2G6	ENST00000594306.1	c.-46+3923C>G		intron_variant	Intron 1 of 1	4		ENSP00000473160.1
ENSG00000298301	ENST00000754572.1	n.184+1916C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78098 AN: 151546 Hom.: 20413 Cov.: 31

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.528

GnomAD4 exome AF: 0.443 AC: 47 AN: 106 Hom.: 11 Cov.: 0 AF XY: 0.412 AC XY: 33 AN XY: 80

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.333 AC: 2 AN: 6

European-Finnish (FIN) AF: 0.625 AC: 10 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.457 AC: 32 AN: 70

Other (OTH) AF: 0.250 AC: 2 AN: 8

GnomAD4 genome AF: 0.515 AC: 78134 AN: 151664 Hom.: 20411 Cov.: 31 AF XY: 0.512 AC XY: 37955 AN XY: 74072

African (AFR) AF: 0.448 AC: 18536 AN: 41334

American (AMR) AF: 0.508 AC: 7753 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1895 AN: 3468

East Asian (EAS) AF: 0.501 AC: 2585 AN: 5162

South Asian (SAS) AF: 0.379 AC: 1820 AN: 4806

European-Finnish (FIN) AF: 0.588 AC: 6170 AN: 10494

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37825 AN: 67834

Other (OTH) AF: 0.524 AC: 1103 AN: 2104

Alfa AF: 0.532 Hom.: 2629

Bravo AF: 0.511

Asia WGS AF: 0.427 AC: 1482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.3
DANN	Benign	0.68
PhyloP100		0.35

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4374456; hg19: chr22-38597377;