Genetic Variant EMC9:p.Glu39Lys (chr14-24141190-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016049.4(EMC9):c.115G>A(p.Glu39Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EMC9
NM_016049.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.28

Publications

0 publications found

Variant links:

Genes affected

EMC9 (HGNC:20273): (ER membrane protein complex subunit 9) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Located in cytoplasm. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

EMC9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0987432).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016049.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EMC9	NM_016049.4	MANE Select	c.115G>A	p.Glu39Lys	missense	Exon 2 of 6	NP_057133.2
EMC9	NM_001346874.2		c.-310G>A		5_prime_UTR	Exon 2 of 6	NP_001333803.1	H0YNH6
EMC9	NM_001346875.2		c.-283G>A		5_prime_UTR	Exon 2 of 6	NP_001333804.1	H0YNH6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EMC9	ENST00000216799.9	TSL:1 MANE Select	c.115G>A	p.Glu39Lys	missense	Exon 2 of 6	ENSP00000216799.4	Q9Y3B6
EMC9	ENST00000419198.6	TSL:1	c.115G>A	p.Glu39Lys	missense	Exon 1 of 5	ENSP00000403210.2	Q9Y3B6
EMC9	ENST00000940002.1		c.115G>A	p.Glu39Lys	missense	Exon 2 of 6	ENSP00000610061.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727184

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.013

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.83

M_CAP

Benign

0.0090

MetaRNN

Benign

0.099

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.11

PhyloP100

3.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.83

REVEL

Benign

0.070

Sift

Benign

0.73

Sift4G

Benign

0.63

Polyphen

0.042

Vest4

0.23

MutPred

0.47

Gain of catalytic residue at L43 (P = 0)

MVP

0.29

MPC

0.24

ClinPred

0.53

GERP RS

3.1

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.24

gMVP

0.48

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over