chr1-19240364-G-A

Position:

chr1-19240364-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015047.3(EMC1):c.719C>T(p.Pro240Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,164 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P240Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 7 hom. )

Consequence

EMC1
NM_015047.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.04

Variant links:

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 links:

EMC1-AS1 (HGNC:):

EMC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005671948).

BP6

Variant 1-19240364-G-A is Benign according to our data. Variant chr1-19240364-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 446000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-19240364-G-A is described in Lovd as [Benign]. Variant chr1-19240364-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00425 (647/152284) while in subpopulation AFR AF= 0.0133 (551/41550). AF 95% confidence interval is 0.0123. There are 1 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC1	NM_015047.3 linkuse as main transcript	c.719C>T	p.Pro240Leu	missense_variant	7/23	ENST00000477853.6	NP_055862.1	Q8N766-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC1	ENST00000477853.6 linkuse as main transcript	c.719C>T	p.Pro240Leu	missense_variant	7/23	1	NM_015047.3	ENSP00000420608.1		Q8N766-1

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

644

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00207

AC:

520

AN:

251430

Hom.:

AF XY:

0.00160

AC XY:

218

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0139

Gnomad AMR exome

AF:

0.00425

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000827

Gnomad OTH exome

AF:

0.00733

GnomAD4 exome

AF:

0.00101

AC:

1476

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000952

AC XY:

692

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.00416

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000577

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.00425

AC:

647

AN:

152284

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.00527

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00220

AC:

267

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0049

T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.063

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.80

T;T;T

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.88

N;N;N

REVEL

Benign

0.029

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.53

P;P;P

Vest4

0.21

MVP

0.37

MPC

0.33

ClinPred

0.011

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.43

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over