8-9011583-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_153332.4(ERI1):c.329A>G(p.Tyr110Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y110H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERI1 NM_153332.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Reduces slightly RNA-binding to the stem-loop structure; when associated with A-109. (size 0) in uniprot entity ERI1_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERI1	NM_153332.4	c.329A>G	p.Tyr110Cys	missense_variant	3/7	ENST00000250263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERI1	ENST00000250263.8	c.329A>G	p.Tyr110Cys	missense_variant	3/7	1	NM_153332.4	P1
ERI1	ENST00000519292.5	c.329A>G	p.Tyr110Cys	missense_variant	3/8	2		P1
ERI1	ENST00000520684.5	c.*136A>G		3_prime_UTR_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Oct 06, 2022

The c.329A>G (p.Y110C) alteration is located in exon 3 (coding exon 3) of the ERI1 gene. This alteration results from a A to G substitution at nucleotide position 329, causing the tyrosine (Y) at amino acid position 110 to be replaced by a cysteine (C). 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	0.15
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.38
MutPred		0.52		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);
MVP		0.56
MPC		0.015
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1407938321; hg19: chr8-8869093;