rs1060499734

Variant names:

• chr6-31780935-G-A
• rs1060499734
• NM_006295.3:c.2653C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_006295.3(VARS1):​c.2653C>T​(p.Leu885Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.38

Genes affected

VARS1 (HGNC:12651): (valyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the VARS1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 2.6849 (below the threshold of 3.09). Trascript score misZ: 3.4812 (above the threshold of 3.09). GenCC associations: The gene is linked to combined oxidative phosphorylation defect type 20, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 6-31780935-G-A is Pathogenic according to our data. Variant chr6-31780935-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402133.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr6-31780935-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS1	NM_006295.3	c.2653C>T	p.Leu885Phe	missense_variant	Exon 23 of 30	ENST00000375663.8	NP_006286.1
VARS1	XM_005249362.3	c.2656C>T	p.Leu886Phe	missense_variant	Exon 23 of 30		XP_005249419.1
VARS1	XM_047419296.1	c.2656C>T	p.Leu886Phe	missense_variant	Exon 22 of 29		XP_047275252.1
VARS1	XM_047419297.1	c.2653C>T	p.Leu885Phe	missense_variant	Exon 22 of 29		XP_047275253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS1	ENST00000375663.8	c.2653C>T	p.Leu885Phe	missense_variant	Exon 23 of 30	1	NM_006295.3	ENSP00000364815.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Pathogenic:1 Uncertain:1

Aug 20, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 20, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous p.Leu885Phe variant in VARS1 was identified by our study in two siblings with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy. This variant has also been reported in two individuals with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (PMIDs: 26539891, 30755616), and has been identified in 0.02% (1/4148) of Middle Eastern chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP (rs1060499734)). Data from large population studies is insufficient to assess the frequency of this variant. Of the 2 affected individuals, both of those were homozygotes, which increases the likelihood that the p.Leu885Phe variant is pathogenic (PMIDs: 26539891, 30755616). This variant has been reported in ClinVar (Variation ID: 402133) and has been interpreted as likely pathogenic by Baylor-Hopkins CMG and pathogenic by OMIM. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The number of missense variants reported in VARS1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, the clinical significance of the p.Leu885Phe variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3, PP2 (Richards 2015). -

Abnormal brain morphology Pathogenic:1

-

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

There is one more families with similar phenotype -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.81		Loss of helix (P = 0.1299);
MVP		0.59
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060499734; hg19: chr6-31748712;