chr15-34228585-C-A

Variant names:

• chr15-34228585-C-A
• rs1890720118
• NM_016454.4:c.512C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016454.4(EMC4):​c.512C>A​(p.Pro171His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EMC4 NM_016454.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• Publications: 0 publications found

Genes affected

EMC4 (HGNC:28032): (ER membrane protein complex subunit 4) 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. Is integral component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016454.4. 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
	EMC4	NM_016454.4	MANE Select	c.512C>A	p.Pro171His	missense	Exon 4 of 5	NP_057538.1	Q5J8M3-1
	EMC4	NM_001351373.2		c.269C>A	p.Pro90His	missense	Exon 4 of 5	NP_001338302.1
	EMC4	NM_001286420.2		c.355+739C>A		intron	N/A	NP_001273349.1	Q5J8M3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC4	ENST00000267750.9	TSL:1 MANE Select	c.512C>A	p.Pro171His	missense	Exon 4 of 5	ENSP00000267750.4	Q5J8M3-1
	EMC4	ENST00000249209.8	TSL:1	c.355+739C>A		intron	N/A	ENSP00000249209.4	Q5J8M3-2
	EMC4	ENST00000854599.1		c.575C>A	p.Pro192His	missense	Exon 4 of 5	ENSP00000524658.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.26
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.34		Loss of glycosylation at P171 (P = 0.0453)
MVP		0.22
MPC		1.4
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.75

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

Other links and lift over

dbSNP: rs1890720118; hg19: chr15-34520786;