8-144105743-T-C

Variant names:

• chr8-144105743-T-C
• rs11136256
• NM_032272.5:c.60T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032272.5(MAF1):​c.60T>C​(p.Thr20Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,613,182 control chromosomes in the GnomAD database, including 793,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (69707 hom., cov: 30)
  • Exomes 𝑓: 1.0 (723874 hom.)
• Consequence: MAF1 NM_032272.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.91
• Publications: 18 publications found

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]

SHARPIN Gene-Disease associations (from GenCC):

• autoinflammation with episodic fever and immune dysregulation

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-144105743-T-C is Benign according to our data. Variant chr8-144105743-T-C is described in ClinVar as Benign. ClinVar VariationId is 403435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAF1	NM_032272.5	c.60T>C	p.Thr20Thr	synonymous_variant	Exon 2 of 8	ENST00000322428.10	NP_115648.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAF1	ENST00000322428.10	c.60T>C	p.Thr20Thr	synonymous_variant	Exon 2 of 8	1	NM_032272.5	ENSP00000318604.5

Frequencies

GnomAD3 genomes AF: 0.954 AC: 145091 AN: 152066 Hom.: 69654 Cov.: 30

Gnomad AFR AF: 0.841

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.982

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.967

GnomAD2 exomes AF: 0.988 AC: 248129 AN: 251182 AF XY: 0.991

Gnomad AFR exome AF: 0.838

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.995 AC: 1453866 AN: 1460998 Hom.: 723874 Cov.: 56 AF XY: 0.996 AC XY: 723654 AN XY: 726792

African (AFR) AF: 0.833 AC: 27889 AN: 33476

American (AMR) AF: 0.991 AC: 44325 AN: 44722

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26135 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86227 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 52569 AN: 52570

Middle Eastern (MID) AF: 0.991 AC: 5717 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111559 AN: 1111988

Other (OTH) AF: 0.989 AC: 59747 AN: 60382

GnomAD4 genome AF: 0.954 AC: 145201 AN: 152184 Hom.: 69707 Cov.: 30 AF XY: 0.956 AC XY: 71122 AN XY: 74406

African (AFR) AF: 0.841 AC: 34881 AN: 41466

American (AMR) AF: 0.982 AC: 15021 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3471 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5168 AN: 5170

South Asian (SAS) AF: 0.999 AC: 4817 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10621 AN: 10622

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67990 AN: 68026

Other (OTH) AF: 0.968 AC: 2034 AN: 2102

Alfa AF: 0.981 Hom.: 86190

Bravo AF: 0.947

Asia WGS AF: 0.991 AC: 3448 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.031
DANN	Benign	0.38
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11136256; hg19: chr8-145160646; COSMIC: COSV59363968; COSMIC: COSV59363968;