Genetic Variant ERICH6B:p.Gly557Ser (chr13-45544963-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182542.3(ERICH6B):c.1669G>A(p.Gly557Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,550,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ERICH6B
NM_182542.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

Variant links:

Genes affected

ERICH6B (HGNC:26523): (glutamate rich 6B)

ERICH6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERICH6B	NM_182542.3 link	c.1669G>A	p.Gly557Ser	missense_variant	Exon 14 of 15	ENST00000298738.3	NP_872348.2	Q5W0A0-1
ERICH6B	XM_011534965.3 link	c.1741G>A	p.Gly581Ser	missense_variant	Exon 13 of 14		XP_011533267.1
ERICH6B	XM_017020418.2 link	c.1669G>A	p.Gly557Ser	missense_variant	Exon 13 of 14		XP_016875907.1	Q5W0A0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERICH6B	ENST00000298738.3 link	c.1669G>A	p.Gly557Ser	missense_variant	Exon 14 of 15	2	NM_182542.3	ENSP00000298738.2	Q5W0A0-1
ERICH6B	ENST00000482992.1 link	n.372G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3
ERICH6B	ENST00000504261.5 link	n.263+4930G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000703

AC:

AN:

156534

Hom.:

AF XY:

0.0000723

AC XY:

AN XY:

82948

show subpopulations

Gnomad AFR exome

AF:

0.000751

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000243

AC:

AN:

1398650

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

689852

show subpopulations

Gnomad4 AFR exome

AF:

0.000728

Gnomad4 AMR exome

AF:

0.000112

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:

0.00000185

Gnomad4 OTH exome

AF:

0.0000863

GnomAD4 genome

AF:

0.000282

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000385

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1669G>A (p.G557S) alteration is located in exon 14 (coding exon 12) of the ERICH6B gene. This alteration results from a G to A substitution at nucleotide position 1669, causing the glycine (G) at amino acid position 557 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.63

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.31

Sift

Uncertain

0.010

Sift4G

Benign

0.097

Polyphen

1.0

Vest4

0.70

MVP

0.095

ClinPred

0.35

GERP RS

3.6

Varity_R

0.34

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over