6-169753866-A-C

Variant names:

• chr6-169753866-A-C
• rs61736820
• NM_018341.3:c.9A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018341.3(ERMARD):​c.9A>C​(p.Val3Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,552,726 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (50 hom.)
• Consequence: ERMARD NM_018341.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0670
• 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, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-169753866-A-C is Benign according to our data. Variant chr6-169753866-A-C is described in ClinVar as Benign. ClinVar VariationId is 384836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.067 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0137 (2081/152222) while in subpopulation AFR AF = 0.0471 (1957/41538). AF 95% confidence interval is 0.0454. There are 43 homozygotes in GnomAd4. There are 1016 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2081 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.9A>C	p.Val3Val	splice_region synonymous	Exon 2 of 18	NP_060811.1	Q5T6L9-1
	ERMARD	NM_001278531.2		c.9A>C	p.Val3Val	splice_region synonymous	Exon 2 of 18	NP_001265460.1	Q5T6L9-3
	ERMARD	NM_001278533.2		c.9A>C	p.Val3Val	splice_region synonymous	Exon 2 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.9A>C	p.Val3Val	splice_region synonymous	Exon 2 of 18	ENSP00000355735.3	Q5T6L9-1
	ERMARD	ENST00000418781.7	TSL:1	c.9A>C	p.Val3Val	splice_region synonymous	Exon 2 of 17	ENSP00000397661.2	Q5T6L9-2
	ERMARD	ENST00000588451.1	TSL:5	c.-370A>C		splice_region	Exon 2 of 17	ENSP00000468240.1	K7ERF7

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2069 AN: 152104 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00364 AC: 656 AN: 180184 AF XY: 0.00248

Gnomad AFR exome AF: 0.0508

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.000245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00143 AC: 2005 AN: 1400504 Hom.: 50 Cov.: 30 AF XY: 0.00118 AC XY: 818 AN XY: 693532

African (AFR) AF: 0.0498 AC: 1533 AN: 30806

American (AMR) AF: 0.00284 AC: 100 AN: 35268

Ashkenazi Jewish (ASJ) AF: 0.000204 AC: 5 AN: 24500

East Asian (EAS) AF: 0.00 AC: 0 AN: 36648

South Asian (SAS) AF: 0.000151 AC: 12 AN: 79546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49552

Middle Eastern (MID) AF: 0.00147 AC: 8 AN: 5430

European-Non Finnish (NFE) AF: 0.0000999 AC: 108 AN: 1081058

Other (OTH) AF: 0.00414 AC: 239 AN: 57696

GnomAD4 genome AF: 0.0137 AC: 2081 AN: 152222 Hom.: 43 Cov.: 32 AF XY: 0.0136 AC XY: 1016 AN XY: 74442

African (AFR) AF: 0.0471 AC: 1957 AN: 41538

American (AMR) AF: 0.00582 AC: 89 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68002

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00448 Hom.: 7

Bravo AF: 0.0162

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.065
DANN	Benign	0.58
PhyloP100		-0.067
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=299/1	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: rs61736820; hg19: chr6-170153962;