18-57601634-C-T

Variant names:

• chr18-57601634-C-T
• rs2070109
• NM_004539.4:c.*18G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004539.4(NARS1):​c.*18G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,609,278 control chromosomes in the GnomAD database, including 22,879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4329 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18550 hom.)
• Consequence: NARS1 NM_004539.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.397
• Publications: 14 publications found

Genes affected

NARS1 (HGNC:7643): (asparaginyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Asparaginyl-tRNA synthetase is localized to the cytoplasm and belongs to the class II family of tRNA synthetases. The N-terminal domain represents the signature sequence for the eukaryotic asparaginyl-tRNA synthetases. [provided by RefSeq, Jul 2008]

NARS1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 18-57601634-C-T is Benign according to our data. Variant chr18-57601634-C-T is described in ClinVar as Benign. ClinVar VariationId is 1290112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004539.4. 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
	NARS1	NM_004539.4	MANE Select	c.*18G>A		3_prime_UTR	Exon 14 of 14	NP_004530.1	O43776-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NARS1	ENST00000256854.10	TSL:1 MANE Select	c.*18G>A		3_prime_UTR	Exon 14 of 14	ENSP00000256854.4	O43776-1
	NARS1	ENST00000925915.1		c.*18G>A		3_prime_UTR	Exon 14 of 14	ENSP00000595974.1
	NARS1	ENST00000902983.1		c.*18G>A		3_prime_UTR	Exon 14 of 14	ENSP00000573042.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32652 AN: 151944 Hom.: 4328 Cov.: 33

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.158 AC: 39419 AN: 250020 AF XY: 0.156

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.153 AC: 223448 AN: 1457216 Hom.: 18550 Cov.: 31 AF XY: 0.152 AC XY: 110476 AN XY: 724906

African (AFR) AF: 0.386 AC: 12845 AN: 33300

American (AMR) AF: 0.108 AC: 4787 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3568 AN: 26034

East Asian (EAS) AF: 0.0962 AC: 3814 AN: 39634

South Asian (SAS) AF: 0.147 AC: 12588 AN: 85922

European-Finnish (FIN) AF: 0.206 AC: 10958 AN: 53314

Middle Eastern (MID) AF: 0.173 AC: 995 AN: 5756

European-Non Finnish (NFE) AF: 0.148 AC: 164160 AN: 1108594

Other (OTH) AF: 0.162 AC: 9733 AN: 60168

GnomAD4 genome AF: 0.215 AC: 32692 AN: 152062 Hom.: 4329 Cov.: 33 AF XY: 0.214 AC XY: 15897 AN XY: 74310

African (AFR) AF: 0.374 AC: 15518 AN: 41456

American (AMR) AF: 0.149 AC: 2277 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 430 AN: 3470

East Asian (EAS) AF: 0.108 AC: 557 AN: 5174

South Asian (SAS) AF: 0.144 AC: 694 AN: 4816

European-Finnish (FIN) AF: 0.221 AC: 2327 AN: 10550

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10227 AN: 68010

Other (OTH) AF: 0.198 AC: 417 AN: 2108

Alfa AF: 0.160 Hom.: 1339

Bravo AF: 0.217

Asia WGS AF: 0.157 AC: 547 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.21
DANN	Benign	0.61
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2070109; hg19: chr18-55268866; COSMIC: COSV56876586; COSMIC: COSV56876586;