14-24140962-C-G

Variant names:

• chr14-24140962-C-G
• rs146171434
• NM_016049.4:c.202G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016049.4(EMC9):​c.202G>C​(p.Asp68His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D68Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EMC9 NM_016049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.33
• Publications: 1 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

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.202G>C	p.Asp68His	missense	Exon 3 of 6	NP_057133.2
	EMC9	NM_001346874.2		c.-223G>C		5_prime_UTR	Exon 3 of 6	NP_001333803.1	H0YNH6
	EMC9	NM_001346875.2		c.-196G>C		5_prime_UTR	Exon 3 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.202G>C	p.Asp68His	missense	Exon 3 of 6	ENSP00000216799.4	Q9Y3B6
	EMC9	ENST00000419198.6	TSL:1	c.202G>C	p.Asp68His	missense	Exon 2 of 5	ENSP00000403210.2	Q9Y3B6
	EMC9	ENST00000940002.1		c.202G>C	p.Asp68His	missense	Exon 3 of 6	ENSP00000610061.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 26136

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: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.96	D
Vest4		0.76
MutPred		0.73		Gain of catalytic residue at Q73 (P = 0)
MVP		0.66
MPC		0.69
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.92
gMVP		0.74
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146171434; hg19: chr14-24610171;