1-19219321-C-G

Position:

• chr1-19219321-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015047.3(EMC1):​c.2964G>C​(p.Leu988=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,872 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (3 hom.)
• Consequence: EMC1 NM_015047.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.391

Genes affected

EMC1 (HGNC:28957): (ER membrane protein complex subunit 1) This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2012]

EMC1-AS1 (HGNC:54050): (EMC1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-19219321-C-G is Benign according to our data. Variant chr1-19219321-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2504057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.391 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000212 (31/1461872) while in subpopulation MID AF= 0.00538 (31/5762). AF 95% confidence interval is 0.00389. There are 3 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMC1	NM_015047.3	c.2964G>C	p.Leu988=	synonymous_variant	23/23	ENST00000477853.6	NP_055862.1
EMC1-AS1	NR_135114.1	n.174+8762C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMC1	ENST00000477853.6	c.2964G>C	p.Leu988=	synonymous_variant	23/23	1	NM_015047.3	ENSP00000420608	P4
EMC1-AS1	ENST00000437898.3	n.212+8762C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461872 Hom.: 3 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727236

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 06, 2023

Variant summary: KIAA0090 c.2964G>C alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251452 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2964G>C in individuals affected with Cerebellar Atrophy, Visual Impairment, And Psychomotor Retardation and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.7
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs764704020; hg19: chr1-19545815;