chr1-19220813-TAGGA-T

Variant names:

• chr1-19220813-TAGGA-T
• rs869320624
• NM_015047.3:c.2619_2622delTCCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015047.3(EMC1):​c.2619_2622delTCCT​(p.Pro874ArgfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: EMC1 NM_015047.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.17
• Publications: 2 publications found

Genes affected

EMC1 (HGNC:28957): (ER membrane protein complex subunit 1) This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2012]

EMC1-AS1 (HGNC:54050): (EMC1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-19220813-TAGGA-T is Pathogenic according to our data. Variant chr1-19220813-TAGGA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015047.3. 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
	EMC1	NM_015047.3	MANE Select	c.2619_2622delTCCT	p.Pro874ArgfsTer21	frameshift	Exon 21 of 23	NP_055862.1	Q8N766-1
	EMC1	NM_001375820.1		c.2628_2631delTCCT	p.Pro877ArgfsTer21	frameshift	Exon 22 of 24	NP_001362749.1	H7C5A2
	EMC1	NM_001375821.1		c.2625_2628delTCCT	p.Pro876ArgfsTer21	frameshift	Exon 22 of 24	NP_001362750.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC1	ENST00000477853.6	TSL:1 MANE Select	c.2619_2622delTCCT	p.Pro874ArgfsTer21	frameshift	Exon 21 of 23	ENSP00000420608.1	Q8N766-1
	EMC1	ENST00000375199.7	TSL:1	c.2616_2619delTCCT	p.Pro873ArgfsTer21	frameshift	Exon 21 of 23	ENSP00000364345.3	Q8N766-2
	EMC1	ENST00000911107.1		c.2723_2726delTCCT	p.Phe908fs	frameshift	Exon 22 of 24	ENSP00000581166.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151596 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151596 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74010

African (AFR) AF: 0.00 AC: 0 AN: 41214

American (AMR) AF: 0.000131 AC: 2 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Cerebellar atrophy, visual impairment, and psychomotor retardation; (1)
1	-	-	Congenital anomaly of kidney and urinary tract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs869320624; hg19: chr1-19547307;