6-169753995-G-C

Position:

• chr6-169753995-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018341.3(ERMARD):​c.138G>C​(p.Trp46Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERMARD	NM_018341.3	c.138G>C	p.Trp46Cys	missense_variant	2/18	ENST00000366773.8	NP_060811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERMARD	ENST00000366773.8	c.138G>C	p.Trp46Cys	missense_variant	2/18	2	NM_018341.3	ENSP00000355735	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ERMARD-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 46 of the ERMARD protein (p.Trp46Cys). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Uncertain	2.5	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Pathogenic	-7.4	D;D;.;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.93
MutPred		0.61		Loss of catalytic residue at W46 (P = 0.0011);Loss of catalytic residue at W46 (P = 0.0011);Loss of catalytic residue at W46 (P = 0.0011);Loss of catalytic residue at W46 (P = 0.0011);
MVP		0.70
MPC		0.30
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1197839775; hg19: chr6-170154091;