1-74572067-C-A

Position:

• chr1-74572067-C-A

Variant summary

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

The NM_001002912.5(ERICH3):​c.3643G>T​(p.Ala1215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ERICH3 NM_001002912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.73

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=0.049756795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERICH3	NM_001002912.5	c.3643G>T	p.Ala1215Ser	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.3643G>T	p.Ala1215Ser	missense_variant	14/15	5	NM_001002912.5	ENSP00000322609	P3
ERICH3	ENST00000433746.2	n.1785G>T		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251126 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461866 Hom.: 0 Cov.: 86 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 12, 2021

The c.3643G>T (p.A1215S) alteration is located in exon 14 (coding exon 14) of the ERICH3 gene. This alteration results from a G to T substitution at nucleotide position 3643, causing the alanine (A) at amino acid position 1215 to be replaced by a serine (S). 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	0.083
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0050
DANN	Benign	0.58
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.0080
Sift	Benign	0.068	T
Sift4G	Benign	0.14	T
Polyphen		0.013	B
Vest4		0.058
MutPred		0.29		Loss of helix (P = 0.0138);
MVP		0.061
MPC		0.019
ClinPred		0.098	T
GERP RS		-7.3
Varity_R		0.039
gMVP		0.038

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: rs780934042; hg19: chr1-75037751; COSMIC: COSV58612604; COSMIC: COSV58612604;