6-169753957-A-G

Variant names:

• chr6-169753957-A-G
• NM_018341.3:c.100A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018341.3(ERMARD):​c.100A>G​(p.Ile34Val) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1818268).

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.100A>G	p.Ile34Val	missense	Exon 2 of 18	NP_060811.1	Q5T6L9-1
	ERMARD	NM_001278531.2		c.100A>G	p.Ile34Val	missense	Exon 2 of 18	NP_001265460.1	Q5T6L9-3
	ERMARD	NM_001278533.2		c.100A>G	p.Ile34Val	missense	Exon 2 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.100A>G	p.Ile34Val	missense	Exon 2 of 18	ENSP00000355735.3	Q5T6L9-1
	ERMARD	ENST00000418781.7	TSL:1	c.100A>G	p.Ile34Val	missense	Exon 2 of 17	ENSP00000397661.2	Q5T6L9-2
	ERMARD	ENST00000588451.1	TSL:5	c.-279A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 17	ENSP00000468240.1	K7ERF7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0097	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.6
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.21
MutPred		0.25		Loss of helix (P = 0.1706)
MVP		0.36
MPC		0.068
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.066
gMVP		0.19
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr6-170154053;