8-9008027-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_153332.4(ERI1):c.166T>C(p.Ser56Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,533,610 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: ERI1 NM_153332.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.26

Genes affected

ERI1 (HGNC:23994): (exoribonuclease 1) Enables 3'-5' exonuclease activity. Predicted to be involved in exonucleolytic trimming to generate mature 3'-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Located in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013551742).
• BP6: Variant 8-9008027-T-C is Benign according to our data. Variant chr8-9008027-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3058455.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERI1	NM_153332.4	c.166T>C	p.Ser56Pro	missense_variant	2/7	ENST00000250263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERI1	ENST00000250263.8	c.166T>C	p.Ser56Pro	missense_variant	2/7	1	NM_153332.4	P1
ERI1	ENST00000519292.5	c.166T>C	p.Ser56Pro	missense_variant	2/8	2		P1
ERI1	ENST00000520684.5	c.166T>C	p.Ser56Pro	missense_variant, NMD_transcript_variant	2/6	5
ERI1	ENST00000521844.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.000904 AC: 122 AN: 134938 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000867

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000693 AC: 174 AN: 251090 Hom.: 0 AF XY: 0.000656 AC XY: 89 AN XY: 135726

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00124 AC: 1735 AN: 1398578 Hom.: 0 Cov.: 35 AF XY: 0.00123 AC XY: 857 AN XY: 694542

Gnomad4 AFR exome AF: 0.000251

Gnomad4 AMR exome AF: 0.0000702

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000265

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.000943

GnomAD4 genome AF: 0.000911 AC: 123 AN: 135032 Hom.: 0 Cov.: 28 AF XY: 0.000810 AC XY: 52 AN XY: 64188

Gnomad4 AFR AF: 0.000135

Gnomad4 AMR AF: 0.0000866

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000140

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00146 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000601 AC: 73

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.166T>C (p.S56P) alteration is located in exon 2 (coding exon 2) of the ERI1 gene. This alteration results from a T to C substitution at nucleotide position 166, causing the serine (S) at amino acid position 56 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ERI1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.074	T;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.46	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.57	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.041	D;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.17
MVP		0.28
MPC		0.0068
ClinPred		0.022	T
GERP RS		3.8
Varity_R		0.30
gMVP		0.12

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: rs150186258; hg19: chr8-8865537;