22-38214847-A-G

Variant names:

• chr22-38214847-A-G
• rs897514249
• NM_012323.4:c.464A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012323.4(MAFF):​c.464A>G​(p.Asp155Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000037 in 1,349,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: MAFF NM_012323.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFF	NM_012323.4	c.464A>G	p.Asp155Gly	missense_variant	Exon 3 of 3	ENST00000338483.7	NP_036455.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAFF	ENST00000338483.7	c.464A>G	p.Asp155Gly	missense_variant	Exon 3 of 3	1	NM_012323.4	ENSP00000345393.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000100 AC: 1 AN: 99634 Hom.: 0 AF XY: 0.0000179 AC XY: 1 AN XY: 55968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000370 AC: 5 AN: 1349552 Hom.: 0 Cov.: 31 AF XY: 0.00000301 AC XY: 2 AN XY: 665522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000377

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464A>G (p.D155G) alteration is located in exon 3 (coding exon 2) of the MAFF gene. This alteration results from a A to G substitution at nucleotide position 464, causing the aspartic acid (D) at amino acid position 155 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.3
DANN	Benign	0.71
DEOGEN2	Benign	0.087	T;.;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.33	.;T;T;.;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.069	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L;.;L;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.46	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.81	T;T;T;T;T
Polyphen		0.0	B;.;B;B;B
Vest4		0.13
MutPred		0.11		Gain of glycosylation at P154 (P = 0.0887);.;Gain of glycosylation at P154 (P = 0.0887);Gain of glycosylation at P154 (P = 0.0887);Gain of glycosylation at P154 (P = 0.0887);
MVP		0.79
MPC		1.7
ClinPred		0.028	T
GERP RS		-6.5
Varity_R		0.044
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs897514249; hg19: chr22-38610854;