19-38915490-G-A

Position:

• chr19-38915490-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017827.4(SARS2):​c.*116C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,294,880 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (26 hom.)
• Consequence: SARS2 NM_017827.4 3_prime_UTR
• Scores: Splicing: ADA: 0.0001582
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.271

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]

ENSG00000269547 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004485935).
• BP6: Variant 19-38915490-G-A is Benign according to our data. Variant chr19-38915490-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 893232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000788 (120/152316) while in subpopulation SAS AF= 0.0236 (114/4822). AF 95% confidence interval is 0.0201. There are 3 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SARS2	NM_017827.4	c.*116C>T		3_prime_UTR_variant	16/16	ENST00000221431.11	NP_060297.1
SARS2	NM_001145901.2	c.*116C>T		3_prime_UTR_variant	17/17		NP_001139373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SARS2	ENST00000221431.11	c.*116C>T		3_prime_UTR_variant	16/16	1	NM_017827.4	ENSP00000221431.6
ENSG00000269547	ENST00000599996	c.*116C>T		3_prime_UTR_variant	20/20	2		ENSP00000472465.1

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00234 AC: 452 AN: 192968 Hom.: 9 AF XY: 0.00337 AC XY: 354 AN XY: 105162

Gnomad AFR exome AF: 0.0000718

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000109

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.00127 AC: 1448 AN: 1142564 Hom.: 26 Cov.: 16 AF XY: 0.00191 AC XY: 1093 AN XY: 573328

Gnomad4 AFR exome AF: 0.0000369

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000467

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74480

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00246 AC: 297

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 13, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	3.3
DANN	Benign	0.52
FATHMM_MKL	Benign	0.090	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0045	T
Sift4G	Uncertain	0.017	D
Vest4		0.11
MVP		0.93
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0020
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: rs563670346; hg19: chr19-39406130;