19-38915507-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017827.4(SARS2):c.*99T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,438,862 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (33 hom.)
• Consequence: SARS2 NM_017827.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.16

Genes affected

SARS2 (HGNC:17697): (seryl-tRNA synthetase 2, mitochondrial) This gene encodes the mitochondrial seryl-tRNA synthethase precursor, a member of the class II tRNA synthetase family. The mature enzyme catalyzes the ligation of Serine to tRNA(Ser) and participates in the biosynthesis of selenocysteinyl-tRNA(sec) in mitochondria. The enzyme contains an N-terminal tRNA binding domain and a core catalytic domain. It functions in a homodimeric form, which is stabilized by tRNA binding. This gene is regulated by a bidirectional promoter that also controls the expression of mitochondrial ribosomal protein S12. Both genes are within the critical interval for the autosomal dominant deafness locus DFNA4 and might be linked to this disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-38915507-A-C is Benign according to our data. Variant chr19-38915507-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 893233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1702/152268) while in subpopulation AFR AF= 0.0356 (1480/41546). AF 95% confidence interval is 0.0341. There are 28 homozygotes in gnomad4. There are 826 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SARS2	NM_017827.4	c.*99T>G		3_prime_UTR_variant	16/16	ENST00000221431.11
SARS2	NM_001145901.2	c.*99T>G		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SARS2	ENST00000221431.11	c.*99T>G		3_prime_UTR_variant	16/16	1	NM_017827.4	P4

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1699 AN: 152150 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00415 AC: 875 AN: 210770 Hom.: 11 AF XY: 0.00324 AC XY: 373 AN XY: 115194

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000970

Gnomad FIN exome AF: 0.0000914

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.00223 AC: 2866 AN: 1286594 Hom.: 33 Cov.: 19 AF XY: 0.00209 AC XY: 1345 AN XY: 642844

Gnomad4 AFR exome AF: 0.0376

Gnomad4 AMR exome AF: 0.00303

Gnomad4 ASJ exome AF: 0.00407

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.0000515

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00370

GnomAD4 genome AF: 0.0112 AC: 1702 AN: 152268 Hom.: 28 Cov.: 32 AF XY: 0.0111 AC XY: 826 AN XY: 74452

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00567 Hom.: 0

Bravo AF: 0.0122

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperuricemia, pulmonary hypertension, renal failure, alkalosis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.6
Dann	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs74399089; hg19: chr19-39406147;