NM_018341.3:c.33_34delAT

Variant names:

• chr6-169753889-CAT-C
• rs747627800
• NM_018341.3:c.33_34delAT

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_018341.3(ERMARD):​c.33_34delAT​(p.Cys12SerfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.000271 in 1,602,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ERMARD NM_018341.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.30

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 Likely_benign. Variant got -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.984 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 6-169753889-CAT-C is Benign according to our data. Variant chr6-169753889-CAT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1711651.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERMARD	NM_018341.3	c.33_34delAT	p.Cys12SerfsTer7	frameshift_variant	Exon 2 of 18	ENST00000366773.8	NP_060811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERMARD	ENST00000366773.8	c.33_34delAT	p.Cys12SerfsTer7	frameshift_variant	Exon 2 of 18	2	NM_018341.3	ENSP00000355735.3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000221 AC: 52 AN: 235504 Hom.: 0 AF XY: 0.000227 AC XY: 29 AN XY: 127582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000576

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000641

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000201

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000285 AC: 413 AN: 1449890 Hom.: 0 AF XY: 0.000275 AC XY: 198 AN XY: 720854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000414

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.000281

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000326

Gnomad4 OTH exome AF: 0.000334

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74308

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000253

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys12Serfs*7) in the ERMARD gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ERMARD cause disease. This variant is present in population databases (rs747627800, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ERMARD-related conditions. ClinVar contains an entry for this variant (Variation ID: 1711651). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ERMARD: BS1 -

Computational scores

Source: dbNSFP v4.3

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: rs747627800; hg19: chr6-170153985;