1-74599757-C-T

Variant names:

• chr1-74599757-C-T
• rs696698
• NM_001002912.5:c.1664G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001002912.5(ERICH3):​c.1664G>A​(p.Arg555His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,611,980 control chromosomes in the GnomAD database, including 2,416 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R555C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.064 (401 hom., cov: 32)
  • Exomes 𝑓: 0.043 (2015 hom.)
• Consequence: ERICH3 NM_001002912.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0480

Genes affected

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

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015816092).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERICH3	NM_001002912.5	c.1664G>A	p.Arg555His	missense_variant	Exon 11 of 15	ENST00000326665.10	NP_001002912.4
ERICH3	XM_017000275.2	c.1658G>A	p.Arg553His	missense_variant	Exon 11 of 14		XP_016855764.1
ERICH3-AS1	NR_121670.1	n.173+9850C>T		intron_variant	Intron 1 of 2
ERICH3-AS1	NR_121671.1	n.81-15449C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERICH3	ENST00000326665.10	c.1664G>A	p.Arg555His	missense_variant	Exon 11 of 15	5	NM_001002912.5	ENSP00000322609.5
ERICH3	ENST00000420661.6	c.1073G>A	p.Arg358His	missense_variant	Exon 6 of 7	1		ENSP00000398581.2
ERICH3-AS1	ENST00000612390.4	n.81-15449C>T		intron_variant	Intron 1 of 2	1
ERICH3-AS1	ENST00000416017.1	n.173+9850C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9739 AN: 151706 Hom.: 400 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0511

Gnomad EAS AF: 0.0608

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0528

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0600

GnomAD3 exomes AF: 0.0617 AC: 15441 AN: 250348 Hom.: 664 AF XY: 0.0622 AC XY: 8415 AN XY: 135370

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0683

Gnomad ASJ exome AF: 0.0548

Gnomad EAS exome AF: 0.0527

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.0575

Gnomad NFE exome AF: 0.0371

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0428 AC: 62485 AN: 1460156 Hom.: 2015 Cov.: 31 AF XY: 0.0450 AC XY: 32710 AN XY: 726428

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.0662

Gnomad4 ASJ exome AF: 0.0516

Gnomad4 EAS exome AF: 0.0695

Gnomad4 SAS exome AF: 0.122

Gnomad4 FIN exome AF: 0.0573

Gnomad4 NFE exome AF: 0.0310

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0643 AC: 9759 AN: 151824 Hom.: 401 Cov.: 32 AF XY: 0.0663 AC XY: 4918 AN XY: 74202

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0492

Gnomad4 ASJ AF: 0.0511

Gnomad4 EAS AF: 0.0606

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.0528

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.0585

Alfa AF: 0.0406 Hom.: 442

Bravo AF: 0.0647

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.105 AC: 462

ESP6500EA AF: 0.0345 AC: 297

ExAC AF: 0.0638 AC: 7750

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.0362

EpiControl AF: 0.0379

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.42
DEOGEN2	Benign	0.0033	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.18	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.34	N;.
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.050
Sift	Benign	0.28	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0	B;B
Vest4		0.088
MPC		0.018
ClinPred		0.00045	T
GERP RS		-1.3
Varity_R		0.022
gMVP		0.018

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: rs696698; hg19: chr1-75065441; COSMIC: COSV58607545;