rs144899015

chr6-169776629-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_018341.3(ERMARD):c.1695G>A(p.Thr565=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,614,190 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (7 hom.)
• Consequence: ERMARD NM_018341.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.18

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-169776629-G-A is Benign according to our data. Variant chr6-169776629-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 384879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS2: High AC in GnomAd at 384 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERMARD	NM_018341.3	c.1695G>A	p.Thr565=	synonymous_variant	16/18	ENST00000366773.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERMARD	ENST00000366773.8	c.1695G>A	p.Thr565=	synonymous_variant	16/18	2	NM_018341.3	P2

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152252 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00885

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

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

GnomAD3 exomes AF: 0.000727 AC: 182 AN: 250190 Hom.: 2 AF XY: 0.000562 AC XY: 76 AN XY: 135328

Gnomad AFR exome AF: 0.00936

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000264 AC: 386 AN: 1461820 Hom.: 7 Cov.: 33 AF XY: 0.000223 AC XY: 162 AN XY: 727206

Gnomad4 AFR exome AF: 0.00929

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152370 Hom.: 2 Cov.: 33 AF XY: 0.00243 AC XY: 181 AN XY: 74510

Gnomad4 AFR AF: 0.00880

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.00297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2016	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

May 28, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	2.1
Dann	Benign	0.75

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: rs144899015; hg19: chr6-170176725;