chr6-169751670-C-T

Variant names:

• chr6-169751670-C-T
• rs3749882
• NM_018341.3:c.6+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018341.3(ERMARD):​c.6+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,554,918 control chromosomes in the GnomAD database, including 16,782 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3013 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13769 hom.)
• Consequence: ERMARD NM_018341.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001121
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.65
• Publications: 8 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]

DYNLT2 (HGNC:11695): (dynein light chain Tctex-type 2) Predicted to enable dynein intermediate chain binding activity. Predicted to be involved in microtubule-based movement. Predicted to be located in cytosol and sperm flagellum. Predicted to be extrinsic component of membrane. Predicted to be part of cytoplasmic dynein complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-169751670-C-T is Benign according to our data. Variant chr6-169751670-C-T is described in ClinVar as Benign. ClinVar VariationId is 380783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

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.6+7C>T		splice_region intron	N/A	NP_060811.1	Q5T6L9-1
	ERMARD	NM_001278531.2		c.6+7C>T		splice_region intron	N/A	NP_001265460.1	Q5T6L9-3
	ERMARD	NM_001278533.2		c.6+7C>T		splice_region intron	N/A	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.6+7C>T		splice_region intron	N/A	ENSP00000355735.3	Q5T6L9-1
	ERMARD	ENST00000418781.7	TSL:1	c.6+7C>T		splice_region intron	N/A	ENSP00000397661.2	Q5T6L9-2
	ERMARD	ENST00000854211.1		c.6+7C>T		splice_region intron	N/A	ENSP00000524270.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27252 AN: 152124 Hom.: 2994 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.0968

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.169 AC: 26920 AN: 159080 AF XY: 0.167

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.131 AC: 183246 AN: 1402674 Hom.: 13769 Cov.: 32 AF XY: 0.132 AC XY: 91528 AN XY: 692658

African (AFR) AF: 0.294 AC: 9369 AN: 31848

American (AMR) AF: 0.219 AC: 7791 AN: 35586

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3288 AN: 25044

East Asian (EAS) AF: 0.294 AC: 10630 AN: 36168

South Asian (SAS) AF: 0.218 AC: 17427 AN: 80022

European-Finnish (FIN) AF: 0.103 AC: 5020 AN: 48868

Middle Eastern (MID) AF: 0.132 AC: 709 AN: 5372

European-Non Finnish (NFE) AF: 0.111 AC: 120595 AN: 1081680

Other (OTH) AF: 0.145 AC: 8417 AN: 58086

GnomAD4 genome AF: 0.179 AC: 27319 AN: 152244 Hom.: 3013 Cov.: 33 AF XY: 0.179 AC XY: 13313 AN XY: 74448

African (AFR) AF: 0.293 AC: 12166 AN: 41542

American (AMR) AF: 0.168 AC: 2571 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1495 AN: 5152

South Asian (SAS) AF: 0.228 AC: 1103 AN: 4828

European-Finnish (FIN) AF: 0.0968 AC: 1028 AN: 10620

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8015 AN: 68004

Other (OTH) AF: 0.183 AC: 387 AN: 2116

Alfa AF: 0.103 Hom.: 370

Bravo AF: 0.191

Asia WGS AF: 0.294 AC: 1022 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.89
CADD	Benign	2.5
DANN	Benign	0.90
PhyloP100		-2.6
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.17		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: rs3749882; hg19: chr6-170151766; COSMIC: COSV64652213; COSMIC: COSV64652213;