rs148450358

Variant names:

• chr6-169755372-C-A
• rs148450358
• NM_018341.3:c.265C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018341.3(ERMARD):​c.265C>A​(p.Gln89Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,614,136 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (7 hom.)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.05
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063410997).
• BP6: Variant 6-169755372-C-A is Benign according to our data. Variant chr6-169755372-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 384878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 376 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.265C>A	p.Gln89Lys	missense	Exon 3 of 18	NP_060811.1	Q5T6L9-1
	ERMARD	NM_001278531.2		c.265C>A	p.Gln89Lys	missense	Exon 3 of 18	NP_001265460.1	Q5T6L9-3
	ERMARD	NM_001278533.2		c.265C>A	p.Gln89Lys	missense	Exon 3 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.265C>A	p.Gln89Lys	missense	Exon 3 of 18	ENSP00000355735.3	Q5T6L9-1
	ERMARD	ENST00000418781.7	TSL:1	c.265C>A	p.Gln89Lys	missense	Exon 3 of 17	ENSP00000397661.2	Q5T6L9-2
	ERMARD	ENST00000854211.1		c.265C>A	p.Gln89Lys	missense	Exon 3 of 19	ENSP00000524270.1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000660 AC: 166 AN: 251470 AF XY: 0.000478

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000250 AC: 366 AN: 1461878 Hom.: 7 Cov.: 31 AF XY: 0.000210 AC XY: 153 AN XY: 727242

African (AFR) AF: 0.00923 AC: 309 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112002

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74454

African (AFR) AF: 0.00869 AC: 361 AN: 41534

American (AMR) AF: 0.000589 AC: 9 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00292

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000782 AC: 95

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	ERMARD-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Benign	0.070	T
Sift4G	Benign	0.093	T
Polyphen		0.78	P
Vest4		0.55
MVP		0.29
MPC		0.10
ClinPred		0.014	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.43
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: rs148450358; hg19: chr6-170155468;