rs869320625

Variant names:

• chr1-19243991-G-A
• rs869320625
• NM_015047.3:c.245C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-19243991-G-A
• chr1-19243991-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_015047.3(EMC1):​c.245C>T​(p.Thr82Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T82T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: EMC1 NM_015047.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 4.93
• Publications: 6 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 Gene-Disease associations (from GenCC):

• cerebellar atrophy, visual impairment, and psychomotor retardation;

  Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• complex neurodevelopmental disorder with motor features

  Inheritance: AR, AD Classification: MODERATE Submitted by: ClinGen
• global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 1-19243991-G-A is Pathogenic according to our data. Variant chr1-19243991-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219100.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.245C>T	p.Thr82Met	missense	Exon 3 of 23	NP_055862.1	Q8N766-1
	EMC1	NM_001375820.1		c.245C>T	p.Thr82Met	missense	Exon 3 of 24	NP_001362749.1	H7C5A2
	EMC1	NM_001375821.1		c.245C>T	p.Thr82Met	missense	Exon 3 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.245C>T	p.Thr82Met	missense	Exon 3 of 23	ENSP00000420608.1	Q8N766-1
	EMC1	ENST00000375199.7	TSL:1	c.245C>T	p.Thr82Met	missense	Exon 3 of 23	ENSP00000364345.3	Q8N766-2
	EMC1	ENST00000911107.1		c.245C>T	p.Thr82Met	missense	Exon 3 of 24	ENSP00000581166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251362 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000327 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Cerebellar atrophy, visual impairment, and psychomotor retardation; (4)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	-	EMC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.15
Sift	Benign	0.034	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.82
MVP		0.78
MPC		0.97
ClinPred		0.77	D
GERP RS		5.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.049
gMVP		0.47
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869320625; hg19: chr1-19570485; COSMIC: COSV100617458; COSMIC: COSV100617458;