rs74451194

chr6-169759023-T-Cchr6-169759023-T-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.563T>C(p.Val188Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000942 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V188I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.79

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=0.019606233).
• BP6: Variant 6-169759023-T-C is Benign according to our data. Variant chr6-169759023-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446063.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERMARD	NM_018341.3	c.563T>C	p.Val188Ala	missense_variant	6/18	ENST00000366773.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERMARD	ENST00000366773.8	c.563T>C	p.Val188Ala	missense_variant	6/18	2	NM_018341.3	P2

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251386 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135866

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461738 Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40 AN XY: 727178

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74496

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000616

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as likely 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.14
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D;T;T;T;D;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.020	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N;N
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D
Polyphen		0.93, 0.89, 0.87	.;P;.;P;.;P;.
Vest4		0.69, 0.72, 0.73
MVP		0.46
MPC		0.098
ClinPred		0.071	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.33

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: rs74451194; hg19: chr6-170159119;