rs143351214

Positions:

• chr6-169773331-G-A
• chr6-169773331-G-C

Variant summary

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

The NM_018341.3(ERMARD):​c.1246G>A​(p.Val416Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,020 control chromosomes in the GnomAD database, including 3 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 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.551

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=0.005703509).
• BP6: Variant 6-169773331-G-A is Benign according to our data. Variant chr6-169773331-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252720.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}. Variant chr6-169773331-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 212 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERMARD	NM_018341.3	c.1246G>A	p.Val416Ile	missense_variant	13/18	ENST00000366773.8	NP_060811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERMARD	ENST00000366773.8	c.1246G>A	p.Val416Ile	missense_variant	13/18	2	NM_018341.3	ENSP00000355735	P2

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00157 AC: 395 AN: 251342 Hom.: 0 AF XY: 0.00164 AC XY: 223 AN XY: 135830

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00485

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00148 AC: 2157 AN: 1461712 Hom.: 3 Cov.: 30 AF XY: 0.00143 AC XY: 1042 AN XY: 727136

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00164

Gnomad4 FIN exome AF: 0.00474

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74478

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00321

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.00131

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 25, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.0090
DANN	Benign	0.27
DEOGEN2	Benign	0.0045	.;.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.0057	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.0	N;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	0.060	N;N;N;N;.
REVEL	Benign	0.014
Sift	Benign	0.91	T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.023	B;.;B;B;.
Vest4		0.21
MVP		0.030
MPC		0.031
ClinPred		0.00049	T
GERP RS		-4.6
Varity_R		0.011
gMVP		0.069

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs143351214; hg19: chr6-170173427;