1-19242478-A-G

Variant names:

• chr1-19242478-A-G
• rs710865
• NM_015047.3:c.381-5T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_015047.3(EMC1):​c.381-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,613,528 control chromosomes in the GnomAD database, including 147,379 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 0.49 (20084 hom., cov: 32)
  • Exomes 𝑓: 0.41 (127295 hom.)
• Consequence: EMC1 NM_015047.3 splice_region, intron
• Scores: Splicing: ADA: 0.01009
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.523
• Publications: 37 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-19242478-A-G is Benign according to our data. Variant chr1-19242478-A-G is described in ClinVar as Benign. ClinVar VariationId is 1166518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC1	NM_015047.3	c.381-5T>C		splice_region_variant, intron_variant	Intron 4 of 22	ENST00000477853.6	NP_055862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC1	ENST00000477853.6	c.381-5T>C		splice_region_variant, intron_variant	Intron 4 of 22	1	NM_015047.3	ENSP00000420608.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73863 AN: 151996 Hom.: 20034 Cov.: 32

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.449

GnomAD2 exomes AF: 0.446 AC: 111894 AN: 251054 AF XY: 0.434

Gnomad AFR exome AF: 0.716

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.723

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.407 AC: 594855 AN: 1461414 Hom.: 127295 Cov.: 41 AF XY: 0.406 AC XY: 295459 AN XY: 727034

African (AFR) AF: 0.725 AC: 24258 AN: 33470

American (AMR) AF: 0.548 AC: 24517 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 8261 AN: 26122

East Asian (EAS) AF: 0.749 AC: 29723 AN: 39694

South Asian (SAS) AF: 0.459 AC: 39611 AN: 86230

European-Finnish (FIN) AF: 0.272 AC: 14548 AN: 53400

Middle Eastern (MID) AF: 0.292 AC: 1673 AN: 5722

European-Non Finnish (NFE) AF: 0.384 AC: 427006 AN: 1111694

Other (OTH) AF: 0.418 AC: 25258 AN: 60366

GnomAD4 genome AF: 0.486 AC: 73974 AN: 152114 Hom.: 20084 Cov.: 32 AF XY: 0.483 AC XY: 35946 AN XY: 74346

African (AFR) AF: 0.708 AC: 29379 AN: 41500

American (AMR) AF: 0.501 AC: 7652 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1081 AN: 3466

East Asian (EAS) AF: 0.722 AC: 3736 AN: 5172

South Asian (SAS) AF: 0.462 AC: 2225 AN: 4820

European-Finnish (FIN) AF: 0.250 AC: 2639 AN: 10570

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25845 AN: 67986

Other (OTH) AF: 0.450 AC: 951 AN: 2114

Alfa AF: 0.421 Hom.: 56255

Bravo AF: 0.517

Asia WGS AF: 0.630 AC: 2188 AN: 3478

EpiCase AF: 0.367

EpiControl AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cerebellar atrophy, visual impairment, and psychomotor retardation; Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.80
PhyloP100		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.18		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: rs710865; hg19: chr1-19568972;