12-6970961-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006331.8(EMG1):c.38G>T(p.Arg13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,054 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (19 hom.)
• Consequence: EMG1 NM_006331.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.64

Genes affected

EMG1 (HGNC:16912): (EMG1 N1-specific pseudouridine methyltransferase) This gene encodes an essential, conserved eukaryotic protein that methylates pseudouridine in 18S rRNA. The related protein in yeast is a component of the small subunit processome and is essential for biogenesis of the ribosomal 40S subunit. A mutation in this gene has been associated with Bowen-Conradi syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036773384).
• BP6: Variant 12-6970961-G-T is Benign according to our data. Variant chr12-6970961-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00797 (1214/152312) while in subpopulation AFR AF= 0.0277 (1152/41560). AF 95% confidence interval is 0.0264. There are 12 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMG1	NM_006331.8	c.38G>T	p.Arg13Leu	missense_variant	1/6	ENST00000599672.6
EMG1	NM_001320049.2	c.38G>T	p.Arg13Leu	missense_variant	1/5
EMG1	NR_135131.2	n.49G>T		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMG1	ENST00000599672.6	c.38G>T	p.Arg13Leu	missense_variant	1/6	1	NM_006331.8	P1
EMG1	ENST00000611981.1	n.49G>T		non_coding_transcript_exon_variant	1/4	2
EMG1	ENST00000620255.1	n.27G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152194 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00198 AC: 488 AN: 246618 Hom.: 10 AF XY: 0.00140 AC XY: 188 AN XY: 133848

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.000817

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000834

GnomAD4 exome AF: 0.000785 AC: 1146 AN: 1460742 Hom.: 19 Cov.: 32 AF XY: 0.000650 AC XY: 472 AN XY: 726564

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152312 Hom.: 12 Cov.: 32 AF XY: 0.00753 AC XY: 561 AN XY: 74482

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00162 Hom.: 4

Bravo AF: 0.00946

ESP6500AA AF: 0.0253 AC: 99

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00242 AC: 293

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	16
Dann	Benign	0.64
DEOGEN2	Benign	0.051	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0037	T
PrimateAI	Benign	0.48	T
Sift4G	Benign	0.38	T
Polyphen		0.11	B
Vest4		0.38
MVP		0.61
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs36061201; hg19: chr12-7080124;