chr15-34228558-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_016454.4(EMC4):​c.485C>T​(p.Ser162Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

EMC4
NM_016454.4 missense

Scores

14
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.945
BS2
High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EMC4NM_016454.4 linkc.485C>T p.Ser162Leu missense_variant Exon 4 of 5 ENST00000267750.9 NP_057538.1 Q5J8M3-1A0A024R9N3
EMC4NM_001351373.2 linkc.242C>T p.Ser81Leu missense_variant Exon 4 of 5 NP_001338302.1
EMC4NM_001286420.2 linkc.355+712C>T intron_variant Intron 3 of 3 NP_001273349.1 Q5J8M3-2A0A0S2Z598
EMC4NR_147140.2 linkn.462+712C>T intron_variant Intron 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EMC4ENST00000267750.9 linkc.485C>T p.Ser162Leu missense_variant Exon 4 of 5 1 NM_016454.4 ENSP00000267750.4 Q5J8M3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461616
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 04, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.485C>T (p.S162L) alteration is located in exon 4 (coding exon 4) of the EMC4 gene. This alteration results from a C to T substitution at nucleotide position 485, causing the serine (S) at amino acid position 162 to be replaced by a leucine (L). 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
0.98
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.24
T
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Uncertain
-0.039
T
MutationAssessor
Pathogenic
3.6
H
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.98
MutPred
0.82
Loss of relative solvent accessibility (P = 0.0981);
MVP
0.47
MPC
1.2
ClinPred
1.0
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.98
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1040431132; hg19: chr15-34520759; API