19-50476608-C-T

Position:

• chr19-50476608-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_206538.4(EMC10):​c.64C>T​(p.Pro22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,409,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: EMC10 NM_206538.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.296

Genes affected

EMC10 (HGNC:27609): (ER membrane protein complex subunit 10) Contributes to membrane insertase activity. Involved in positive regulation of angiogenesis; positive regulation of endothelial cell proliferation; and protein insertion into ER membrane. Located in extracellular region. Is integral component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

GARIN5A (HGNC:25107): (golgi associated RAB2 interactor 5A)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13411793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC10	NM_206538.4	c.64C>T	p.Pro22Ser	missense_variant	1/7	ENST00000334976.11	NP_996261.1
GARIN5A	NM_001308429.2	c.-220G>A		5_prime_UTR_variant	1/5	ENST00000600100.6	NP_001295358.1
EMC10	NM_175063.6	c.64C>T	p.Pro22Ser	missense_variant	1/8		NP_778233.4
GARIN5A	NM_138411.3	c.-220G>A		5_prime_UTR_variant	1/5		NP_612420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC10	ENST00000334976.11	c.64C>T	p.Pro22Ser	missense_variant	1/7	1	NM_206538.4	ENSP00000334037	A2
GARIN5A	ENST00000600100.6	c.-220G>A		5_prime_UTR_variant	1/5	1	NM_001308429.2	ENSP00000472421	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1409434 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 697894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.64C>T (p.P22S) alteration is located in exon 1 (coding exon 1) of the EMC10 gene. This alteration results from a C to T substitution at nucleotide position 64, causing the proline (P) at amino acid position 22 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	.;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.77	N;N;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.11	N;N;.
REVEL	Benign	0.019
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.35	B;B;.
Vest4		0.34
MutPred		0.23		Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);
MVP		0.34
MPC		0.14
ClinPred		0.46	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1010515037; hg19: chr19-50979865;