NM_016049.4:c.115G>A

Variant names:

• chr14-24141190-C-T
• rs1594364586
• NM_016049.4:c.115G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28
• Publications: 0 publications found

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]

ACMG classification

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

Sel.	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

Sel.	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.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461744 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727184

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N
PhyloP100		3.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.070
Sift	Benign	0.73	T
Sift4G	Benign	0.63	T
Polyphen		0.042	B
Vest4		0.23
MutPred		0.47		Gain of catalytic residue at L43 (P = 0)
MVP		0.29
MPC		0.24
ClinPred		0.53	D
GERP RS		3.1
PromoterAI		-0.044	Neutral
Varity_R		0.24
gMVP		0.48
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1594364586; hg19: chr14-24610399;