chr15-34101611-A-C

Position:

• chr15-34101611-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The ENST00000256545.9(EMC7):​c.229T>G​(p.Phe77Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EMC7 ENST00000256545.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.27

Genes affected

EMC7 (HGNC:24301): (ER membrane protein complex subunit 7) 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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC7	NM_020154.3	c.229T>G	p.Phe77Val	missense_variant	1/5	ENST00000256545.9	NP_064539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC7	ENST00000256545.9	c.229T>G	p.Phe77Val	missense_variant	1/5	1	NM_020154.3	ENSP00000256545	P1
EMC7	ENST00000527822.5	c.199T>G	p.Phe67Val	missense_variant	1/4	2		ENSP00000434292
EMC7	ENST00000528949.1	c.17+154T>G		intron_variant		3		ENSP00000434496
EMC7	ENST00000532113.1	n.217T>G		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 58 AN: 151394 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000461

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000780

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00153

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.000958

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0264 AC: 37880 AN: 1434778 Hom.: 0 Cov.: 31 AF XY: 0.0251 AC XY: 17906 AN XY: 714404

Gnomad4 AFR exome AF: 0.0235

Gnomad4 AMR exome AF: 0.00573

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.00774

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0299

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000389 AC: 59 AN: 151512 Hom.: 0 Cov.: 31 AF XY: 0.000459 AC XY: 34 AN XY: 74002

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000782

Gnomad4 SAS AF: 0.000420

Gnomad4 FIN AF: 0.00153

Gnomad4 NFE AF: 0.000295

Gnomad4 OTH AF: 0.000948

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 18, 2024

The c.229T>G (p.F77V) alteration is located in exon 1 (coding exon 1) of the EMC7 gene. This alteration results from a T to G substitution at nucleotide position 229, causing the phenylalanine (F) at amino acid position 77 to be replaced by a valine (V). 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	0.94
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.86		Loss of stability (P = 0.1124);
MVP		0.54
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.73

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: rs1901174527; hg19: chr15-34393812;