Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_018341.3(ERMARD):c.1130T>A(p.Ile377Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I377F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ERMARD
NM_018341.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.55

Publications

1 publications found

Variant links:

Genes affected

ERMARD (HGNC:21056): (ER membrane associated RNA degradation) The protein encoded by this gene contains 2 transmembrane domains near the C-terminus and is localized in the endoplasmic reticulum. Knockout of this gene in developing rat brain showed that it may be involved in neuronal migration. Mutations in this gene are associated with periventricular nodular heterotopia-6 (PVNH6). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2013]

ERMARD Gene-Disease associations (from GenCC):

periventricular nodular heterotopia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
periventricular nodular heterotopia 6
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ERMARD links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

PP5

Variant 6-169769610-T-A is Pathogenic according to our data. Variant chr6-169769610-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 88869.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018341.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERMARD	NM_018341.3	MANE Select	c.1130T>A	p.Ile377Asn	missense	Exon 12 of 18	NP_060811.1
ERMARD	NM_001278531.2		c.1130T>A	p.Ile377Asn	missense	Exon 12 of 18	NP_001265460.1
ERMARD	NM_001278533.2		c.1130T>A	p.Ile377Asn	missense	Exon 12 of 17	NP_001265462.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERMARD	ENST00000366773.8	TSL:2 MANE Select	c.1130T>A	p.Ile377Asn	missense	Exon 12 of 18	ENSP00000355735.3
ERMARD	ENST00000418781.7	TSL:1	c.1130T>A	p.Ile377Asn	missense	Exon 12 of 17	ENSP00000397661.2
ERMARD	ENST00000366772.6	TSL:5	c.1130T>A	p.Ile377Asn	missense	Exon 12 of 18	ENSP00000355734.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Periventricular nodular heterotopia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

Eigen

Benign

-0.057

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

PhyloP100

3.6

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.71

Sift

Benign

0.073

Sift4G

Benign

0.11

Polyphen

0.091

Vest4

0.73

MutPred

0.39

Gain of relative solvent accessibility (P = 0.0082)

MVP

0.40

MPC

0.23

ClinPred

0.97

GERP RS

5.3

Varity_R

0.40

gMVP

0.55

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over