chr16-70289223-C-T

Variant names:

• chr16-70289223-C-T
• rs34087264
• NM_001605.3:c.-22+198G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001605.3(AARS1):​c.-22+198G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,838 control chromosomes in the GnomAD database, including 13,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.42 (13687 hom., cov: 30)
• Consequence: AARS1 NM_001605.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.427
• Publications: 19 publications found

Genes affected

AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

AARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2N

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• developmental and epileptic encephalopathy, 29

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• trichothiodystrophy 8, nonphotosensitive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-70289223-C-T is Benign according to our data. Variant chr16-70289223-C-T is described in ClinVar as Benign. ClinVar VariationId is 1248821.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS1	NM_001605.3	c.-22+198G>A		intron_variant	Intron 1 of 20	ENST00000261772.13	NP_001596.2
AARS1	XM_047433666.1	c.-22+198G>A		intron_variant	Intron 1 of 15		XP_047289622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13	c.-22+198G>A		intron_variant	Intron 1 of 20	1	NM_001605.3	ENSP00000261772.8

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64220 AN: 151720 Hom.: 13675 Cov.: 30

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.427

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.423 AC: 64270 AN: 151838 Hom.: 13687 Cov.: 30 AF XY: 0.425 AC XY: 31515 AN XY: 74232

African (AFR) AF: 0.415 AC: 17177 AN: 41394

American (AMR) AF: 0.386 AC: 5884 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1595 AN: 3468

East Asian (EAS) AF: 0.419 AC: 2141 AN: 5114

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4814

European-Finnish (FIN) AF: 0.525 AC: 5540 AN: 10562

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29149 AN: 67914

Other (OTH) AF: 0.426 AC: 900 AN: 2112

Alfa AF: 0.425 Hom.: 5706

Bravo AF: 0.417

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.2
DANN	Benign	0.79
PhyloP100		-0.43
PromoterAI		-0.025	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34087264; hg19: chr16-70323126;