chr1-74606873-T-G

Position:

• chr1-74606873-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001002912.5(ERICH3):​c.1217A>C​(p.Lys406Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ERICH3 NM_001002912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

Genes affected

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

ERICH3-AS1 (HGNC:41093): (ERICH3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3173172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERICH3	NM_001002912.5	c.1217A>C	p.Lys406Thr	missense_variant	10/15	ENST00000326665.10	NP_001002912.4
ERICH3	XM_017000275.2	c.1211A>C	p.Lys404Thr	missense_variant	10/14		XP_016855764.1
ERICH3-AS1	NR_121670.1	n.174-8333T>G		intron_variant
ERICH3-AS1	NR_121671.1	n.81-8333T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERICH3	ENST00000326665.10	c.1217A>C	p.Lys406Thr	missense_variant	10/15	5	NM_001002912.5	ENSP00000322609.5
ERICH3	ENST00000420661.6	c.626A>C	p.Lys209Thr	missense_variant	5/7	1		ENSP00000398581.2
ERICH3-AS1	ENST00000612390.4	n.81-8333T>G		intron_variant		1
ERICH3-AS1	ENST00000416017.1	n.174-8333T>G		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460268 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726490

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: 0.00

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

Jul 26, 2022

The c.1217A>C (p.K406T) alteration is located in exon 10 (coding exon 10) of the ERICH3 gene. This alteration results from a A to C substitution at nucleotide position 1217, causing the lysine (K) at amino acid position 406 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.6	M;.
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.31
MutPred		0.28		Loss of methylation at K406 (P = 0.0019);.;
MVP		0.23
MPC		0.11
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-75072557;