19-50476614-C-T

Position:

chr19-50476614-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_206538.4(EMC10):c.70C>T(p.Arg24Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000032 in 1,560,824 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 Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

EMC10
NM_206538.4 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -0.482

Variant links:

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]

EMC10 links:

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

GARIN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.911 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-50476614-C-T is Pathogenic according to our data. Variant chr19-50476614-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1320121.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EMC10	NM_206538.4 linkuse as main transcript	c.70C>T	p.Arg24Ter	stop_gained	1/7	ENST00000334976.11	NP_996261.1
GARIN5A	NM_001308429.2 linkuse as main transcript	c.-226G>A		5_prime_UTR_variant	1/5	ENST00000600100.6	NP_001295358.1
EMC10	NM_175063.6 linkuse as main transcript	c.70C>T	p.Arg24Ter	stop_gained	1/8		NP_778233.4
GARIN5A	NM_138411.3 linkuse as main transcript	c.-226G>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 linkuse as main transcript	c.70C>T	p.Arg24Ter	stop_gained	1/7	1	NM_206538.4	ENSP00000334037	A2	Q5UCC4-1
GARIN5A	ENST00000600100.6 linkuse as main transcript	c.-226G>A		5_prime_UTR_variant	1/5	1	NM_001308429.2	ENSP00000472421	A2	Q6IPT2-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000585

AC:

AN:

170814

Hom.:

AF XY:

0.0000105

AC XY:

AN XY:

94856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000220

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1408606

Hom.:

Cov.:

AF XY:

0.00000430

AC XY:

AN XY:

697422

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000539

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

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:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with dysmorphic facies and variable seizures

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Oct 02, 2021

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000058, PM2). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

EMC10-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

The EMC10 c.70C>T variant is predicted to result in premature protein termination (p.Arg24*). To our knowledge this variant has not been reported in the literature. This variant is reported in 1 out ~171,000 of alleles in individuals in gnomAD (Other Population). Nonsense variants in EMC10 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.022

FATHMM_MKL

Benign

0.16

MutationTaster

Benign

1.0

A;A;D;D

Vest4

0.090

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over