rs74399089

Variant names:

• chr19-38915507-A-C
• rs74399089
• NM_017827.4:c.*99T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38915507-A-C
• chr19-38915507-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16
• Publications: 2 publications found

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]

SARS2 Gene-Disease associations (from GenCC):

• hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000269547 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 893233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017827.4. 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
	SARS2	NM_017827.4	MANE Select	c.*99T>G		3_prime_UTR	Exon 16 of 16	NP_060297.1	Q9NP81-1
	SARS2	NM_001145901.2		c.*99T>G		3_prime_UTR	Exon 17 of 17	NP_001139373.1	Q9NP81-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SARS2	ENST00000221431.11	TSL:1 MANE Select	c.*99T>G		3_prime_UTR	Exon 16 of 16	ENSP00000221431.6	Q9NP81-1
	ENSG00000269547	ENST00000599996.1	TSL:2	c.*99T>G		3_prime_UTR	Exon 20 of 20	ENSP00000472465.1	M0R2C6
	SARS2	ENST00000897494.1		c.*99T>G		3_prime_UTR	Exon 16 of 16	ENSP00000567553.1

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

GnomAD2 exomes AF: 0.00415 AC: 875 AN: 210770 AF XY: 0.00324

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 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

African (AFR) AF: 0.0376 AC: 1126 AN: 29908

American (AMR) AF: 0.00303 AC: 121 AN: 39986

Ashkenazi Jewish (ASJ) AF: 0.00407 AC: 93 AN: 22846

East Asian (EAS) AF: 0.00 AC: 0 AN: 38658

South Asian (SAS) AF: 0.000847 AC: 67 AN: 79100

European-Finnish (FIN) AF: 0.0000515 AC: 2 AN: 38866

Middle Eastern (MID) AF: 0.0110 AC: 41 AN: 3722

European-Non Finnish (NFE) AF: 0.00124 AC: 1215 AN: 979242

Other (OTH) AF: 0.00370 AC: 201 AN: 54266

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

African (AFR) AF: 0.0356 AC: 1480 AN: 41546

American (AMR) AF: 0.00542 AC: 83 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68010

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00628 Hom.: 1

Bravo AF: 0.0122

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperuricemia, pulmonary hypertension, renal failure, alkalosis syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.6
DANN	Benign	0.42
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs74399089; hg19: chr19-39406147;