Genetic Variant NM_015047.3:c.719C>T (chr1-19240364-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:6

Conservation

PhyloP100: 2.04

Publications

12 publications found

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:54050): (EMC1 antisense RNA 1)

EMC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 446000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EMC1	NM_015047.3	MANE Select	c.719C>T	p.Pro240Leu	missense	Exon 7 of 23	NP_055862.1	Q8N766-1
EMC1	NM_001375820.1		c.719C>T	p.Pro240Leu	missense	Exon 7 of 24	NP_001362749.1	H7C5A2
EMC1	NM_001375821.1		c.719C>T	p.Pro240Leu	missense	Exon 7 of 24	NP_001362750.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EMC1	ENST00000477853.6	TSL:1 MANE Select	c.719C>T	p.Pro240Leu	missense	Exon 7 of 23	ENSP00000420608.1	Q8N766-1
EMC1	ENST00000375199.7	TSL:1	c.719C>T	p.Pro240Leu	missense	Exon 7 of 23	ENSP00000364345.3	Q8N766-2
EMC1	ENST00000911107.1		c.719C>T	p.Pro240Leu	missense	Exon 7 of 24	ENSP00000581166.1

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

GnomAD2 exomes

AF:

0.00207

AC:

520

AN:

251430

AF XY:

0.00160

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 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

African (AFR)

AF:

0.0134

AC:

450

AN:

33478

American (AMR)

AF:

0.00416

AC:

186

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000577

AC:

642

AN:

1112000

Other (OTH)

AF:

0.00258

AC:

156

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00425

AC:

647

AN:

152284

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0133

AC:

551

AN:

41550

American (AMR)

AF:

0.00301

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68026

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00197

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0049

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.063

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

2.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.88

REVEL

Benign

0.029

Sift

Benign

0.18

Sift4G

Benign

0.36

Polyphen

0.53

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

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over