chr16-85799289-C-A

Position:

• chr16-85799289-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006067.5(EMC8):​c.7G>T​(p.Gly3Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,601,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EMC8 NM_006067.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

Genes affected

EMC8 (HGNC:7864): (ER membrane protein complex subunit 8) 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 cytosol. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

COX4I1 (HGNC:2265): (cytochrome c oxidase subunit 4I1) Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer and proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit IV isoform 1 of the human mitochondrial respiratory chain enzyme. It is located at the 3' of the NOC4 (neighbor of COX4) gene in a head-to-head orientation, and shares a promoter with it. Pseudogenes related to this gene are located on chromosomes 13 and 14. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2978147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC8	NM_006067.5	c.7G>T	p.Gly3Trp	missense_variant	1/5	ENST00000253457.8	NP_006058.1
EMC8	NM_001142288.2	c.7G>T	p.Gly3Trp	missense_variant	1/4		NP_001135760.1
EMC8	XM_011522813.4	c.7G>T	p.Gly3Trp	missense_variant	1/5		XP_011521115.1
EMC8	XR_001751817.3	n.256G>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC8	ENST00000253457.8	c.7G>T	p.Gly3Trp	missense_variant	1/5	1	NM_006067.5	ENSP00000253457.3
EMC8	ENST00000435200.2	c.7G>T	p.Gly3Trp	missense_variant	1/4	2		ENSP00000391730.1
COX4I1	ENST00000565078.5	c.-2+221C>A		intron_variant		4		ENSP00000454869.1
EMC8	ENST00000596852.1	n.108G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449266 Hom.: 0 Cov.: 30 AF XY: 0.00000416 AC XY: 3 AN XY: 720654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

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

Oct 03, 2024

The c.7G>T (p.G3W) alteration is located in exon 1 (coding exon 1) of the EMC8 gene. This alteration results from a G to T substitution at nucleotide position 7, causing the glycine (G) at amino acid position 3 to be replaced by a tryptophan (W). 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	Benign	0.31
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.91	P;.
Vest4		0.30
MutPred		0.51		Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);
MVP		0.41
MPC		0.93
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.63

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: rs769707012; hg19: chr16-85832895;