Genetic Variant ERICH3:p.Arg555His (chr1-74599757-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/20 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 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0480

Publications

15 publications found

Variant links:

Genes affected

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

ERICH3 links:

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

ERICH3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 link	c.1664G>A	p.Arg555His	missense_variant	Exon 11 of 15	ENST00000326665.10	NP_001002912.4	Q5RHP9-1
ERICH3	XM_017000275.2 link	c.1658G>A	p.Arg553His	missense_variant	Exon 11 of 14		XP_016855764.1
ERICH3-AS1	NR_121670.1 link	n.173+9850C>T		intron_variant	Intron 1 of 2
ERICH3-AS1	NR_121671.1 link	n.81-15449C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERICH3	ENST00000326665.10 link	c.1664G>A	p.Arg555His	missense_variant	Exon 11 of 15	5	NM_001002912.5	ENSP00000322609.5	Q5RHP9-1
ERICH3	ENST00000420661.6 link	c.1073G>A	p.Arg358His	missense_variant	Exon 6 of 7	1		ENSP00000398581.2	Q5RHP9-3
ERICH3-AS1	ENST00000612390.4 link	n.81-15449C>T		intron_variant	Intron 1 of 2	1
ERICH3-AS1	ENST00000416017.1 link	n.173+9850C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0642

AC:

9739

AN:

151706

Hom.:

400

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0617

AC:

15441

AN:

250348

AF XY:

0.0622

show subpopulations

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 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.:

AF XY:

0.0450

AC XY:

32710

AN XY:

726428

show subpopulations

African (AFR)

AF:

0.123

AC:

4105

AN:

33344

American (AMR)

AF:

0.0662

AC:

2948

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.0516

AC:

1343

AN:

26038

East Asian (EAS)

AF:

0.0695

AC:

2759

AN:

39670

South Asian (SAS)

AF:

0.122

AC:

10468

AN:

86118

European-Finnish (FIN)

AF:

0.0573

AC:

3058

AN:

53382

Middle Eastern (MID)

AF:

0.0537

AC:

309

AN:

5752

European-Non Finnish (NFE)

AF:

0.0310

AC:

34424

AN:

1111006

Other (OTH)

AF:

0.0509

AC:

3071

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3074

6148

9221

12295

15369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1392

2784

4176

5568

6960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0643

AC:

9759

AN:

151824

Hom.:

401

Cov.:

AF XY:

0.0663

AC XY:

4918

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.116

AC:

4805

AN:

41448

American (AMR)

AF:

0.0492

AC:

748

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.0511

AC:

177

AN:

3466

East Asian (EAS)

AF:

0.0606

AC:

311

AN:

5136

South Asian (SAS)

AF:

0.131

AC:

629

AN:

4812

European-Finnish (FIN)

AF:

0.0528

AC:

559

AN:

10596

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0352

AC:

2388

AN:

67844

Other (OTH)

AF:

0.0585

AC:

123

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

465

930

1396

1861

2326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0441

Hom.:

912

Bravo

AF:

0.0647

TwinsUK

AF:

0.0237

AC:

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

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.8

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.0033

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.18

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.34

N;.

PhyloP100

0.048

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

GERP RS

-1.3

Varity_R

0.022

gMVP

0.018

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over