1-19243991-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_015047.3(EMC1):​c.245C>G​(p.Thr82Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T82M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EMC1 NM_015047.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.93
• Publications: 0 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: AD, AR 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC1	NM_015047.3	MANE Select	c.245C>G	p.Thr82Arg	missense	Exon 3 of 23	NP_055862.1
	EMC1	NM_001375820.1		c.245C>G	p.Thr82Arg	missense	Exon 3 of 24	NP_001362749.1
	EMC1	NM_001375821.1		c.245C>G	p.Thr82Arg	missense	Exon 3 of 24	NP_001362750.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC1	ENST00000477853.6	TSL:1 MANE Select	c.245C>G	p.Thr82Arg	missense	Exon 3 of 23	ENSP00000420608.1
	EMC1	ENST00000375199.7	TSL:1	c.245C>G	p.Thr82Arg	missense	Exon 3 of 23	ENSP00000364345.3
	EMC1	ENST00000486405.2	TSL:2	c.245C>G	p.Thr82Arg	missense	Exon 3 of 24	ENSP00000419345.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 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: 0.00 AC: 0 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: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0071	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.42	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.079
Sift	Benign	0.12	T
Sift4G	Benign	0.38	T
Polyphen		0.64	P
Vest4		0.54
MutPred		0.32		Loss of helix (P = 0.0167)
MVP		0.71
MPC		0.81
ClinPred		0.82	D
GERP RS		5.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.18
gMVP		0.52
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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;