22-38214753-G-C

Variant names:

• chr22-38214753-G-C
• rs899693402
• NM_012323.4:c.370G>C

Variant summary

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

The NM_012323.4(MAFF):​c.370G>C​(p.Ala124Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000024 in 1,252,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: MAFF NM_012323.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.788

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=0.19523978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFF	NM_012323.4	c.370G>C	p.Ala124Pro	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.370G>C	p.Ala124Pro	missense_variant	Exon 3 of 3	1	NM_012323.4	ENSP00000345393.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000240 AC: 3 AN: 1252320 Hom.: 0 Cov.: 31 AF XY: 0.00000163 AC XY: 1 AN XY: 615314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000730

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.80e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.075	T;.;T;T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.67	.;T;T;T;.;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L;.;L;.;L;L
PROVEAN	Benign	0.43	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.060	T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;D;T;T
Polyphen		0.0030	B;.;B;.;B;B
Vest4		0.21
MutPred		0.31		Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.93
MPC		1.7
ClinPred		0.041	T
GERP RS		-2.4
Varity_R		0.090
gMVP		0.55

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: rs899693402; hg19: chr22-38610760;