12-6971024-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006331.8(EMG1):c.101C>G(p.Ala34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,611,376 control chromosomes in the GnomAD database, including 1,281 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.028 (89 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1192 hom.)
• Consequence: EMG1 NM_006331.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019704998).
• BP6: Variant 12-6971024-C-G is Benign according to our data. Variant chr12-6971024-C-G is described in ClinVar as [Benign]. Clinvar id is 218683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6971024-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0285 (4334/152172) while in subpopulation NFE AF= 0.0402 (2731/68002). AF 95% confidence interval is 0.0389. There are 89 homozygotes in gnomad4. There are 2153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 89 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMG1	NM_006331.8	c.101C>G	p.Ala34Gly	missense_variant	1/6	ENST00000599672.6
EMG1	NM_001320049.2	c.101C>G	p.Ala34Gly	missense_variant	1/5
EMG1	NR_135131.2	n.112C>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMG1	ENST00000599672.6	c.101C>G	p.Ala34Gly	missense_variant	1/6	1	NM_006331.8	P1
EMG1	ENST00000611981.1	n.112C>G		non_coding_transcript_exon_variant	1/4	2
EMG1	ENST00000620255.1	n.90C>G		non_coding_transcript_exon_variant	1/2	2
EMG1	ENST00000539196.2			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4336 AN: 152052 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.00652

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0801

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0301 AC: 7059 AN: 234174 Hom.: 149 AF XY: 0.0297 AC XY: 3776 AN XY: 127172

Gnomad AFR exome AF: 0.00600

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.0000591

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0321

GnomAD4 exome AF: 0.0376 AC: 54889 AN: 1459204 Hom.: 1192 Cov.: 32 AF XY: 0.0367 AC XY: 26630 AN XY: 725624

Gnomad4 AFR exome AF: 0.00505

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.0752

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0357

GnomAD4 genome AF: 0.0285 AC: 4334 AN: 152172 Hom.: 89 Cov.: 32 AF XY: 0.0289 AC XY: 2153 AN XY: 74396

Gnomad4 AFR AF: 0.00650

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.0801

Gnomad4 NFE AF: 0.0402

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0340 Hom.: 32

Bravo AF: 0.0231

TwinsUK AF: 0.0448 AC: 166

ALSPAC AF: 0.0423 AC: 163

ESP6500AA AF: 0.00493 AC: 19

ESP6500EA AF: 0.0398 AC: 328

ExAC AF: 0.0285 AC: 3442

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Feb 13, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Benign	0.73
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0020	T
PrimateAI	Benign	0.40	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.16
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.36

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: rs11064480; hg19: chr12-7080187;