rs398122410

Positions:

• chr6-169769610-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 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).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 88869.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-169769610-T-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERMARD	NM_018341.3	c.1130T>A	p.Ile377Asn	missense_variant	12/18	ENST00000366773.8	NP_060811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERMARD	ENST00000366773.8	c.1130T>A	p.Ile377Asn	missense_variant	12/18	2	NM_018341.3	ENSP00000355735	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Periventricular nodular heterotopia 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M;.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Pathogenic	-4.5	D;D;D;D;.
REVEL	Pathogenic	0.71
Sift	Benign	0.073	T;T;T;T;.
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.091	B;.;B;D;.
Vest4		0.73
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);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

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: rs398122410; hg19: chr6-170169706;