chr1-74571277-A-G

Variant names:

• chr1-74571277-A-G
• NM_001002912.5:c.4433T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001002912.5(ERICH3):​c.4433T>C​(p.Leu1478Ser) 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. 15/21 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: -0.566
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062128216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERICH3	NM_001002912.5	c.4433T>C	p.Leu1478Ser	missense_variant	Exon 14 of 15	ENST00000326665.10	NP_001002912.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERICH3	ENST00000326665.10	c.4433T>C	p.Leu1478Ser	missense_variant	Exon 14 of 15	5	NM_001002912.5	ENSP00000322609.5
ERICH3	ENST00000433746.2	n.2575T>C		non_coding_transcript_exon_variant	Exon 2 of 3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4433T>C (p.L1478S) alteration is located in exon 14 (coding exon 14) of the ERICH3 gene. This alteration results from a T to C substitution at nucleotide position 4433, causing the leucine (L) at amino acid position 1478 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	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.1
DANN	Benign	0.72
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.57
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.0020
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Polyphen		0.058	B
Vest4		0.16
MutPred		0.15		Gain of phosphorylation at L1478 (P = 0.0026);
MVP		0.055
MPC		0.020
ClinPred		0.058	T
GERP RS		-1.6
Varity_R		0.051
gMVP		0.047
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

hg19: chr1-75036961;