chr6-169769642-A-G

Variant names:

• chr6-169769642-A-G
• rs151283330
• NM_018341.3:c.1162A>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.1162A>G​(p.Asn388Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,612,910 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: ERMARD NM_018341.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.438
• Publications: 3 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, LIMITED Submitted by: ClinGen, Orphanet
• periventricular nodular heterotopia 6

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004989624).
• BP6: Variant 6-169769642-A-G is Benign according to our data. Variant chr6-169769642-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377111.
• BS2: High AC in GnomAd4 at 418 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERMARD	NM_018341.3	MANE Select	c.1162A>G	p.Asn388Asp	missense	Exon 12 of 18	NP_060811.1	Q5T6L9-1
	ERMARD	NM_001278531.2		c.1162A>G	p.Asn388Asp	missense	Exon 12 of 18	NP_001265460.1	Q5T6L9-3
	ERMARD	NM_001278533.2		c.1162A>G	p.Asn388Asp	missense	Exon 12 of 17	NP_001265462.1	Q5T6L9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERMARD	ENST00000366773.8	TSL:2 MANE Select	c.1162A>G	p.Asn388Asp	missense	Exon 12 of 18	ENSP00000355735.3	Q5T6L9-1
	ERMARD	ENST00000418781.7	TSL:1	c.1162A>G	p.Asn388Asp	missense	Exon 12 of 17	ENSP00000397661.2	Q5T6L9-2
	ERMARD	ENST00000854211.1		c.1162A>G	p.Asn388Asp	missense	Exon 12 of 19	ENSP00000524270.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00268 AC: 670 AN: 249630 AF XY: 0.00256

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00834

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00417 AC: 6087 AN: 1460622 Hom.: 18 Cov.: 31 AF XY: 0.00405 AC XY: 2942 AN XY: 726544

African (AFR) AF: 0.000836 AC: 28 AN: 33474

American (AMR) AF: 0.00236 AC: 105 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00766 AC: 200 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000396 AC: 34 AN: 85856

European-Finnish (FIN) AF: 0.00116 AC: 62 AN: 53388

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00487 AC: 5414 AN: 1111450

Other (OTH) AF: 0.00401 AC: 242 AN: 60368

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74482

African (AFR) AF: 0.000794 AC: 33 AN: 41562

American (AMR) AF: 0.00196 AC: 30 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00451 AC: 307 AN: 68008

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00372 Hom.: 2

Bravo AF: 0.00277

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00232 AC: 282

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00399

EpiControl AF: 0.00422

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	ERMARD-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.0
DANN	Benign	0.94
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.44
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.036
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.13
MVP		0.076
MPC		0.036
ClinPred		0.0040	T
GERP RS		-6.7
Varity_R		0.096
gMVP		0.37
Mutation Taster		=99/1	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: rs151283330; hg19: chr6-170169738; COSMIC: COSV99060621; COSMIC: COSV99060621;