rs11537663

Variant names:

• chr16-70252647-T-A
• rs11537663
• NM_001605.3:c.*74A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-70252647-T-A
• chr16-70252647-T-G

Variant summary

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

The NM_001605.3(AARS1):​c.*74A>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 0.0676 in 1,549,306 control chromosomes in the GnomAD database, including 3,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (300 hom., cov: 33)
  • Exomes 𝑓: 0.069 (3629 hom.)
• Consequence: AARS1 NM_001605.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.417
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-70252647-T-A is Benign according to our data. Variant chr16-70252647-T-A is described in ClinVar as [Benign]. Clinvar id is 320323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS1	NM_001605.3	c.*74A>T		3_prime_UTR_variant	Exon 21 of 21	ENST00000261772.13	NP_001596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13	c.*74A>T		3_prime_UTR_variant	Exon 21 of 21	1	NM_001605.3	ENSP00000261772.8

Frequencies

GnomAD3 genomes AF: 0.0594 AC: 9041 AN: 152100 Hom.: 300 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0604

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0667

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.0746

GnomAD4 exome AF: 0.0685 AC: 95702 AN: 1397088 Hom.: 3629 Cov.: 23 AF XY: 0.0688 AC XY: 48102 AN XY: 698702

African (AFR) AF: 0.0384 AC: 1235 AN: 32182

American (AMR) AF: 0.0448 AC: 1998 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 1591 AN: 25728

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39422

South Asian (SAS) AF: 0.0722 AC: 6085 AN: 84228

European-Finnish (FIN) AF: 0.0724 AC: 3678 AN: 50768

Middle Eastern (MID) AF: 0.0803 AC: 342 AN: 4258

European-Non Finnish (NFE) AF: 0.0725 AC: 76721 AN: 1057720

Other (OTH) AF: 0.0696 AC: 4049 AN: 58176

GnomAD4 genome AF: 0.0594 AC: 9038 AN: 152218 Hom.: 300 Cov.: 33 AF XY: 0.0603 AC XY: 4486 AN XY: 74398

African (AFR) AF: 0.0383 AC: 1592 AN: 41550

American (AMR) AF: 0.0604 AC: 923 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 203 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0670 AC: 323 AN: 4822

European-Finnish (FIN) AF: 0.0781 AC: 828 AN: 10602

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0722 AC: 4908 AN: 67982

Other (OTH) AF: 0.0734 AC: 155 AN: 2112

Alfa AF: 0.0334 Hom.: 24

Bravo AF: 0.0574

Asia WGS AF: 0.0290 AC: 102 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2N Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.68
PhyloP100		-0.42
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: rs11537663; hg19: chr16-70286550; COSMIC: COSV55747087; COSMIC: COSV55747087;