rs74451194

Variant names:

• chr6-169759023-T-C
• rs74451194
• NM_018341.3:c.563T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-169759023-T-C
• chr6-169759023-T-G

Variant summary

Our verdict is Benign. The variant received -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:2 B:2
• Conservation: PhyloP100: 3.79
• Publications: 1 publications found

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]

ERMARD Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• periventricular nodular heterotopia 6

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 446063.
• BS2: High AC in GnomAd4 at 74 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018341.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERMARD	NM_018341.3	MANE Select	c.563T>C	p.Val188Ala	missense	Exon 6 of 18	NP_060811.1
	ERMARD	NM_001278531.2		c.563T>C	p.Val188Ala	missense	Exon 6 of 18	NP_001265460.1
	ERMARD	NM_001278533.2		c.563T>C	p.Val188Ala	missense	Exon 6 of 17	NP_001265462.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERMARD	ENST00000366773.8	TSL:2 MANE Select	c.563T>C	p.Val188Ala	missense	Exon 6 of 18	ENSP00000355735.3
	ERMARD	ENST00000418781.7	TSL:1	c.563T>C	p.Val188Ala	missense	Exon 6 of 17	ENSP00000397661.2
	ERMARD	ENST00000366772.6	TSL:5	c.563T>C	p.Val188Ala	missense	Exon 6 of 18	ENSP00000355734.1

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

GnomAD2 exomes AF: 0.000143 AC: 36 AN: 251386 AF XY: 0.000110

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 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

African (AFR) AF: 0.00200 AC: 67 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.000149 AC: 9 AN: 60390

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

African (AFR) AF: 0.00166 AC: 69 AN: 41558

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000224 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	1	ERMARD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.8
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.93	P
Vest4		0.69
MVP		0.46
MPC		0.098
ClinPred		0.071	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.33
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs74451194; hg19: chr6-170159119;