15-34228460-G-C

Position:

• chr15-34228460-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016454.4(EMC4):​c.387G>C​(p.Lys129Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 3.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMC4	NM_016454.4	c.387G>C	p.Lys129Asn	missense_variant	4/5	ENST00000267750.9
EMC4	NM_001351373.2	c.144G>C	p.Lys48Asn	missense_variant	4/5
EMC4	NM_001286420.2	c.355+614G>C		intron_variant
EMC4	NR_147140.2	n.462+614G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMC4	ENST00000267750.9	c.387G>C	p.Lys129Asn	missense_variant	4/5	1	NM_016454.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2024

The c.387G>C (p.K129N) alteration is located in exon 4 (coding exon 4) of the EMC4 gene. This alteration results from a G to C substitution at nucleotide position 387, causing the lysine (K) at amino acid position 129 to be replaced by an asparagine (N). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.87	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.069
Sift	Benign	0.39	T
Sift4G	Benign	0.50	T
Polyphen		0.17	B
Vest4		0.42
MutPred		0.40		Loss of methylation at K129 (P = 0.0067);
MVP		0.11
MPC		0.52
ClinPred		0.42	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-34520661;