NM_018341.3:c.1130T>A

Variant names:

• chr6-169769610-T-A
• rs398122410
• NM_018341.3:c.1130T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.55
• Publications: 1 publications found

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, LIMITED Submitted by: ClinGen, Orphanet
• periventricular nodular heterotopia 6

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERMARD	NM_018341.3	MANE Select	c.1130T>A	p.Ile377Asn	missense	Exon 12 of 18	NP_060811.1	Q5T6L9-1
	ERMARD	NM_001278531.2		c.1130T>A	p.Ile377Asn	missense	Exon 12 of 18	NP_001265460.1	Q5T6L9-3
	ERMARD	NM_001278533.2		c.1130T>A	p.Ile377Asn	missense	Exon 12 of 17	NP_001265462.1	Q5T6L9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERMARD	ENST00000366773.8	TSL:2 MANE Select	c.1130T>A	p.Ile377Asn	missense	Exon 12 of 18	ENSP00000355735.3	Q5T6L9-1
	ERMARD	ENST00000418781.7	TSL:1	c.1130T>A	p.Ile377Asn	missense	Exon 12 of 17	ENSP00000397661.2	Q5T6L9-2
	ERMARD	ENST00000854211.1		c.1130T>A	p.Ile377Asn	missense	Exon 12 of 19	ENSP00000524270.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	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	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.6
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.71
Sift	Benign	0.073	T
Sift4G	Benign	0.11	T
Polyphen		0.091	B
Vest4		0.73
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.40
MPC		0.23
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.40
gMVP		0.55
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122410; hg19: chr6-170169706;