rs1252011196

Variant names:

• chr6-169754002-A-G
• rs1252011196
• NM_018341.3:c.145A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018341.3(ERMARD):​c.145A>G​(p.Ile49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0150
• 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: Orphanet, ClinGen
• periventricular nodular heterotopia 6

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048140526).
• BS2: High AC in GnomAd4 at 6 AD,Unknown gene.

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.145A>G	p.Ile49Val	missense	Exon 2 of 18	NP_060811.1	Q5T6L9-1
	ERMARD	NM_001278531.2		c.145A>G	p.Ile49Val	missense	Exon 2 of 18	NP_001265460.1	Q5T6L9-3
	ERMARD	NM_001278533.2		c.145A>G	p.Ile49Val	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.145A>G	p.Ile49Val	missense	Exon 2 of 18	ENSP00000355735.3	Q5T6L9-1
	ERMARD	ENST00000418781.7	TSL:1	c.145A>G	p.Ile49Val	missense	Exon 2 of 17	ENSP00000397661.2	Q5T6L9-2
	ERMARD	ENST00000854211.1		c.145A>G	p.Ile49Val	missense	Exon 2 of 19	ENSP00000524270.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251160 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461280 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726948

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000112 AC: 5 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111668

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000393 AC: 6 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions as Germline

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	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.13
DANN	Benign	0.67
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.015
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.0090
Sift	Benign	0.13	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.23		Gain of sheet (P = 0.0344)
MVP		0.095
MPC		0.030
ClinPred		0.066	T
GERP RS		-1.6
Varity_R		0.021
gMVP		0.17
Mutation Taster		=298/2	polymorphism

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: rs1252011196; hg19: chr6-170154098;