rs748697004

Variant names:

• chr8-144106935-G-A
• rs748697004
• NM_032272.5:c.721G>A

Variant summary

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

The NM_032272.5(MAF1):​c.721G>A​(p.Glu241Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 1,514,940 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: MAF1 NM_032272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.886

Genes affected

MAF1 (HGNC:24966): (MAF1 homolog, negative regulator of RNA polymerase III) This gene encodes a protein that is similar to Maf1, a Saccharomyces cerevisiae protein highly conserved in eukaryotic cells. Yeast Maf1 is a negative effector of RNA polymerase III (Pol III). It responds to changes in the cellular environment and represses pol III transcription. Biochemical studies identified the initiation factor TFIIIB as a target for Maf1-dependent repression. [provided by RefSeq, Jul 2008]

SHARPIN (HGNC:25321): (SHANK associated RH domain interactor) Enables polyubiquitin modification-dependent protein binding activity. Involved in protein linear polyubiquitination and regulation of signal transduction. Located in cytosol. Part of LUBAC complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.07959315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAF1	NM_032272.5	c.721G>A	p.Glu241Lys	missense_variant	Exon 7 of 8	ENST00000322428.10	NP_115648.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAF1	ENST00000322428.10	c.721G>A	p.Glu241Lys	missense_variant	Exon 7 of 8	1	NM_032272.5	ENSP00000318604.5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152172 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000645 AC: 9 AN: 139622 Hom.: 0 AF XY: 0.0000274 AC XY: 2 AN XY: 73076

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000328

Gnomad SAS exome AF: 0.0000682

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000643

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000536 AC: 73 AN: 1362768 Hom.: 0 Cov.: 66 AF XY: 0.0000583 AC XY: 39 AN XY: 668830

Gnomad4 AFR exome AF: 0.0000664

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000135

Gnomad4 SAS exome AF: 0.0000559

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000573

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152172 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000995 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000417 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721G>A (p.E241K) alteration is located in exon 7 (coding exon 6) of the MAF1 gene. This alteration results from a G to A substitution at nucleotide position 721, causing the glutamic acid (E) at amino acid position 241 to be replaced by a lysine (K). 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	0.082
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;T;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;.;N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.56	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.030	D;D;D;D
Sift4G	Benign	0.75	T;T;T;D
Polyphen		0.0030	B;.;B;.
Vest4		0.27
MutPred		0.19		Gain of ubiquitination at E241 (P = 4e-04);.;Gain of ubiquitination at E241 (P = 4e-04);.;
MVP		0.26
MPC		0.0053
ClinPred		0.024	T
GERP RS		2.5
Varity_R		0.10
gMVP		0.22

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: rs748697004; hg19: chr8-145161838;