15-34228585-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC4	NM_016454.4	c.512C>A	p.Pro171His	missense_variant	Exon 4 of 5	ENST00000267750.9	NP_057538.1
EMC4	NM_001351373.2	c.269C>A	p.Pro90His	missense_variant	Exon 4 of 5		NP_001338302.1
EMC4	NM_001286420.2	c.355+739C>A		intron_variant	Intron 3 of 3		NP_001273349.1
EMC4	NR_147140.2	n.462+739C>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC4	ENST00000267750.9	c.512C>A	p.Pro171His	missense_variant	Exon 4 of 5	1	NM_016454.4	ENSP00000267750.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.512C>A (p.P171H) alteration is located in exon 4 (coding exon 4) of the EMC4 gene. This alteration results from a C to A substitution at nucleotide position 512, causing the proline (P) at amino acid position 171 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs1890720118; hg19: chr15-34520786;