rs151283330

chr6-169769642-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018341.3(ERMARD):c.1162A>G(p.Asn388Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,612,910 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.438

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004989624).
• BP6: Variant 6-169769642-A-G is Benign according to our data. Variant chr6-169769642-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377111.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=1, Uncertain_significance=1}. Variant chr6-169769642-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 418 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERMARD	NM_018341.3	c.1162A>G	p.Asn388Asp	missense_variant	12/18	ENST00000366773.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERMARD	ENST00000366773.8	c.1162A>G	p.Asn388Asp	missense_variant	12/18	2	NM_018341.3	P2

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00268 AC: 670 AN: 249630 Hom.: 2 AF XY: 0.00256 AC XY: 345 AN XY: 135014

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00834

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000463

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00417 AC: 6087 AN: 1460622 Hom.: 18 Cov.: 31 AF XY: 0.00405 AC XY: 2942 AN XY: 726544

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.00766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000396

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00487

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74482

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00451

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00416 Hom.: 1

Bravo AF: 0.00277

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00232 AC: 282

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00399

EpiControl AF: 0.00422

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ERMARD: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

ERMARD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	1.0
Dann	Benign	0.94
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.62	T;T;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0050	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L;.;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	-2.1	N;N;N;N;.
REVEL	Benign	0.036
Sift	Benign	0.11	T;T;T;T;.
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.0020	B;.;B;B;.
Vest4		0.13
MVP		0.076
MPC		0.036
ClinPred		0.0040	T
GERP RS		-6.7
Varity_R		0.096
gMVP		0.37

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: rs151283330; hg19: chr6-170169738; COSMIC: COSV99060621; COSMIC: COSV99060621;