NM_206538.4:c.259C>T

Variant names:

• chr19-50479028-C-T
• rs1008544115
• NM_206538.4:c.259C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_206538.4(EMC10):​c.259C>T​(p.Gln87*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,458,090 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: EMC10 NM_206538.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.96
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with dysmorphic facies and variable seizures

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: G2P
• global developmental delay with or without impaired intellectual development

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-50479028-C-T is Pathogenic according to our data. Variant chr19-50479028-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1704221.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206538.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC10	NM_206538.4	MANE Select	c.259C>T	p.Gln87*	stop_gained	Exon 3 of 7	NP_996261.1	Q5UCC4-1
	EMC10	NM_175063.6		c.259C>T	p.Gln87*	stop_gained	Exon 3 of 8	NP_778233.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC10	ENST00000334976.11	TSL:1 MANE Select	c.259C>T	p.Gln87*	stop_gained	Exon 3 of 7	ENSP00000334037.6	Q5UCC4-1
	EMC10	ENST00000376918.7	TSL:1	c.259C>T	p.Gln87*	stop_gained	Exon 3 of 8	ENSP00000366117.2	Q5UCC4-2
	EMC10	ENST00000601780.5	TSL:1	n.*195C>T		non_coding_transcript_exon	Exon 3 of 8	ENSP00000470164.1	M0QYY4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000815 AC: 2 AN: 245454 AF XY: 0.00000751

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458090 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 725166

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4264

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111214

Other (OTH) AF: 0.0000166 AC: 1 AN: 60152

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with dysmorphic facies and variable seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		4.0
Vest4		0.22
GERP RS		3.9
Mutation Taster		=9/191	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1008544115; hg19: chr19-50982285;