1-74571371-C-T

Position:

• chr1-74571371-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001002912.5(ERICH3):​c.4339G>A​(p.Glu1447Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 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)
• Consequence: ERICH3 NM_001002912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

ERICH3 (HGNC:25346): (glutamate rich 3)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064912856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERICH3	NM_001002912.5	c.4339G>A	p.Glu1447Lys	missense_variant	14/15	ENST00000326665.10	NP_001002912.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERICH3	ENST00000326665.10	c.4339G>A	p.Glu1447Lys	missense_variant	14/15	5	NM_001002912.5	ENSP00000322609	P3
ERICH3	ENST00000433746.2	n.2481G>A		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 22, 2022

The c.4339G>A (p.E1447K) alteration is located in exon 14 (coding exon 14) of the ERICH3 gene. This alteration results from a G to A substitution at nucleotide position 4339, causing the glutamic acid (E) at amino acid position 1447 to be replaced by a lysine (K). 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	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.76	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.058
Sift	Benign	0.064	T
Sift4G	Uncertain	0.044	D
Polyphen		0.19	B
Vest4		0.11
MutPred		0.22		Gain of ubiquitination at E1447 (P = 7e-04);
MVP		0.081
MPC		0.022
ClinPred		0.31	T
GERP RS		3.8
Varity_R		0.098
gMVP		0.059

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: rs1646941480; hg19: chr1-75037055;