7-140459203-T-C

Variant summary

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

The NM_013446.4(MKRN1):c.575A>G(p.Gln192Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,636 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: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MKRN1 NM_013446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66

Genes affected

MKRN1 (HGNC:7112): (makorin ring finger protein 1) This gene encodes a protein that belongs to a novel class of zinc finger proteins. The encoded protein functions as a transcriptional co-regulator, and as an E3 ubiquitin ligase that promotes the ubiquitination and proteasomal degradation of target proteins. The protein encoded by this gene is thought to regulate RNA polymerase II-catalyzed transcription. Substrates for this protein's E3 ubiquitin ligase activity include the capsid protein of the West Nile virus and the catalytic subunit of the telomerase ribonucleoprotein. This protein controls cell cycle arrest and apoptosis by regulating p21, a cell cycle regulator, and the tumor suppressor protein p53. Pseudogenes of this gene are present on chromosomes 1, 3, 9, 12 and 20, and on the X chromosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]

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=0.11971557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKRN1	NM_013446.4	c.575A>G	p.Gln192Arg	missense_variant	4/8	ENST00000255977.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKRN1	ENST00000255977.7	c.575A>G	p.Gln192Arg	missense_variant	4/8	1	NM_013446.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 250934 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461636 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000403

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000576 AC: 7

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

May 06, 2022

The c.575A>G (p.Q192R) alteration is located in exon 4 (coding exon 4) of the MKRN1 gene. This alteration results from a A to G substitution at nucleotide position 575, causing the glutamine (Q) at amino acid position 192 to be replaced by an arginine (R). 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	0.094
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.;.;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.075
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D;D;T;D;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.9	L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.20	T;T;T;D;D;D
Sift4G	Benign	0.14	T;T;T;T;D;T
Polyphen		0.083	B;.;.;.;.;.
Vest4		0.46
MutPred		0.18		Loss of methylation at K197 (P = 0.0813);.;Loss of methylation at K197 (P = 0.0813);.;.;.;
MVP		0.77
MPC		0.25
ClinPred		0.10	T
GERP RS		2.5
Varity_R		0.097
gMVP		0.38

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: rs747179489; hg19: chr7-140159003;