22-38214745-T-C

Position:

• chr22-38214745-T-C

Variant summary

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

The NM_012323.4(MAFF):​c.362T>C​(p.Val121Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAFF NM_012323.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAFF	NM_012323.4	c.362T>C	p.Val121Ala	missense_variant	3/3	ENST00000338483.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAFF	ENST00000338483.7	c.362T>C	p.Val121Ala	missense_variant	3/3	1	NM_012323.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1259680 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 619048

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2023

The c.362T>C (p.V121A) alteration is located in exon 3 (coding exon 2) of the MAFF gene. This alteration results from a T to C substitution at nucleotide position 362, causing the valine (V) at amino acid position 121 to be replaced by an alanine (A). 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	0.31
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.24	T;.;T;T;T;T;T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.75	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.4	M;.;M;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.77	N;N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.059	T;T;T;D;D;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T;T
Polyphen		0.56	P;.;P;.;.;P;P
Vest4		0.047
MutPred		0.35		Gain of disorder (P = 0.0257);.;Gain of disorder (P = 0.0257);.;Gain of disorder (P = 0.0257);Gain of disorder (P = 0.0257);Gain of disorder (P = 0.0257);
MVP		0.99
MPC		1.6
ClinPred		0.79	D
GERP RS		3.8
Varity_R		0.12
gMVP		0.65

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: rs1769644375; hg19: chr22-38610752;